What this is
- Circadian rhythms are vital for regulating various physiological processes in organisms.
- The core circadian clock gene plays a significant role in maintaining these rhythms and is implicated in multiple diseases.
- This review discusses 's biological characteristics, regulatory mechanisms, and its involvement in cardiovascular, neurological, metabolic, immune-related diseases, and tumors.
Essence
- is a key circadian clock gene that regulates physiological homeostasis and influences the progression of various diseases, including cardiovascular, neurological, and metabolic disorders.
Key takeaways
- regulates blood pressure and renal function, particularly in salt-sensitive hypertension. Its dysregulation may contribute to cardiovascular disease progression.
- In neurological disorders, influences ischemic brain injury and sleep homeostasis, with genetic variants linked to conditions like Parkinson's disease.
- also modulates metabolic processes, including glucose and lipid metabolism, and plays a role in immune responses and tumor suppression.
Caveats
- Most findings are based on animal models or cell studies, with limited clinical validation for 's role in human diseases.
- The specific mechanisms of in different tissues and diseases remain incompletely understood, necessitating further research.
Definitions
- circadian rhythm: An inherent 24-hour periodic rhythm in organisms, regulating various physiological processes.
- PER1: A core circadian clock gene involved in maintaining circadian rhythms and influencing multiple diseases.
AI simplified
Introduction
Biological rhythms are widely present in various life activities in nature. They are endogenous rhythmic life activities that organisms have gradually formed during their occurrence and evolution over hundreds of millions of years to adapt to environmental changes, which are similar to the periodic changes of the natural environment. In short, biological rhythms are the core mechanism for organisms to adapt to the environment, achieving dynamic balance between physiology, behavior and the environment through precise time regulation. Biological rhythms include annual rhythms, monthly rhythms and circadian rhythms. Circadian rhythm is an important biological rhythm, which is the inherent 24-hour periodic rhythm in organisms and is maintained by a highly conserved molecular rhythm device - the biological clock (1). The biological clock is an intrinsic time-regulating system that influences the physiology and behavior of organisms by regulating periodic changes in gene expression (2, 3). A variety of physiological functions of organisms, such as sleep-wake cycles, metabolism, endocrine, immunity, body temperature and cognition, as well as the functional operation of various systems, are all precisely regulated by circadian rhythms (4–6).
The central regulatory hub of circadian rhythms resides within the suprachiasmatic nucleus (SCN) of the hypothalamus. Functioning as the “master clock,” the SCN receives photic inputs via the retinohypothalamic tract, thereby achieving synchronization with the Earth’s 24-hour light-dark cycle. Through the secretion of neurotransmitters (e.g., vasoactive intestinal peptide), the SCN orchestrates rhythmicity across peripheral tissues throughout the organism (7). Beyond the SCN, autonomous molecular circadian oscillators are present in most peripheral tissues (such as the liver and lungs), which maintain synchronization with the central clock through neurohumoral signaling (8). At the molecular level, circadian rhythms are driven by a transcription-translation feedback loop (TTFL) consisting of core clock genes, including brain and muscle arnt-like 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), PER, and cryptochrome (CRY). These genes generate molecular oscillations with a periodicity of approximately 24 hours via time-delayed feedback regulation (9).
The discovery of the PER1 gene, a core circadian clock regulatory gene, can be traced back to homologous studies on the Period gene in Drosophila, making it one of the earliest identified core clock genes (10). As a crucial component of the circadian clock, PER1 not only participates in maintaining normal circadian rhythms but also plays a significant role in the pathogenesis of various diseases (11). In recent years, the roles of PER1 in cancer, cardiovascular diseases, metabolic disorders, neurodegenerative diseases, and immune-related diseases have been gradually unveiled. Its molecular mechanisms involve multiple levels, including cell cycle regulation, metabolic pathway intervention, and immune response modulation, thus emerging as a key target in interdisciplinary research (Figure 1). Starting from the biological functions of PER1, this article reviews its roles, pathophysiological significance, and related molecular mechanisms in cardiovascular diseases, neurodegenerative diseases, metabolic disorders, immune-related diseases, and cancer. Additionally, we distinguished levels of evidence and cross-species conservation of mechanism, aiming to provide new insights and targets for disease prevention and treatment.
Role and mechanism ofin diseases. PER1
Biological characteristics and regulatory mechanisms of PER1
Core components of the circadian negative feedback loop
PER1 is localized on human chromosome 17p13.1 and encodes a nuclear protein containing a PAS domain. As a key component of the TTFL, PER1 works in conjunction with other circadian clock genes to maintain the body’s circadian rhythm. The core of the molecular mechanism underlying the circadian clock is an autonomous oscillatory system composed of TTFL, in which PER proteins, together with CLOCK, BMAL1, and CRY proteins, form a core regulatory network (12, 13). Period circadian regulator serves as a core regulatory factor in the negative feedback loop of the mammalian circadian clock, and together with CLOCK, BMAL1, CRY RAR-related orphan receptors (RORs), and nuclear receptor subfamily 1 group D member 1 (NR1D1), it regulates the circadian rhythmicity of physiological activities in the organism.
As a pair of transcriptional activators, CLOCK and BMAL1 form a CLOCK-BMAL1 heterodimer, which binds to the E-box in the promoter region to activate the transcription of PER and CRY genes. When PER and CRY proteins reach a certain concentration in the cytoplasm, they form a dimer, translocate into the nucleus, and then inhibit the transcriptional activity of the CLOCK-BMAL1 heterodimer. This negative feedback mechanism ensures the timely suppression of PER and CRY transcription, thereby maintaining the stable operation of the circadian clock (14–16). At the level of species evolution, the PER gene family has generated multiple paralogous genes (e.g., PER1/PER2/PER3) in vertebrates through gene duplication events. Among them, PER1 plays a critical role in maintaining rhythm plasticity, and its cis-regulatory elements exhibit characteristics of rapid evolution across different lineages (17, 18).
Rhythmicity and tissue-specificity ofexpression PER1
The expression of PER1 exhibits variations across individuals of different ages and genders, with distinct temporal fluctuations throughout a 24-hour period (19). Accumulating evidence indicates that PER1 expression follows a well-defined circadian pattern. For example, in human peripheral blood, PER1 expression displays a diurnal phase, peaking at 9:00 AM and remaining low during nighttime (11), Similarly, PER1 messenger RNA (mRNA) levels are downregulated between Zeitgeber time (ZT) 0–2 and reach maximal expression between ZT 12–14 (20).
The expression of PER1 is not confined to SCN, the primary circadian pacemaker, but is widely distributed across peripheral tissues and cells. Its expression levels and functional roles are tissue-specific, contributing to the specific regulation of local tissues. For instance, within the SCN, PER1 can respond to light stimuli and participate in the regulation of circadian rhythms. In peripheral tissues such as the liver and kidneys, PER1 controls physiological rhythms by regulating gene expression, thereby influencing metabolic processes, body temperature, blood pressure, and other physiological functions. In tumors, the low expression of PER1 may be associated with the regulation of tumor cell proliferation, invasion, and apoptosis (21–23).
Regulatory mechanisms of PER1
The stability of PER1 is regulated by casein kinase 1 (CK1), which modulates its degradation rate through phosphorylation of specific domains (e.g., D1 and D2) in PER1, thereby determining the length of the circadian period. The phosphorylation status of PER1 (such as CK1-mediated phosphorylation) influences its stability and the transcription of downstream genes, which holds significant pathological implications in various diseases (24, 25). Far upstream element-binding protein 1 maintains circadian rhythm stability by regulating the rhythmic expression of PER1 protein; its depletion leads to disruptions in the oscillatory pattern of PER1 protein (26). The mRNA expression of PER1 is negatively regulated by fragile X mental retardation protein (FMRP), and the absence of FMRP results in disturbances in the oscillation of PER1 protein (27).
Studies have demonstrated that the expression of PER1 is significantly influenced by external environmental factors (such as light exposure and nutritional status) and genetic variations. For example, light can regulate PER1 expression in the SCN via the retinohypothalamic tract, while time-restricted feeding affects the oscillation of PER1 in peripheral tissues by modulating intestinal hormones and metabolic signals (28–31). PER1 is also dynamically regulated by hormones, receptors, and other metabolites. Specifically, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) bind to the PER1 promoter in a periodic manner, dynamically regulating PER1 transcription through the formation of homodimers or heterodimers (32); acute stimulation with glucocorticoids can directly induce PER1 mRNA expression (33–35); and cellular iron levels can also modulate PER1 expression (36).
In summary, PER1 protein exhibits a distinct circadian expression pattern, with its expression levels precisely regulated by phosphorylation, epigenetic modifications, external environment, hormones, and receptor signals. It exerts tissue-specific functions in both central and peripheral tissues, participating in the regulation of fundamental life processes such as cellular metabolism, proliferation, and differentiation, and thus holds significant implications in various diseases.
Role and mechanism ofin diseases PER1
Recent studies have revealed that abnormal expression or functional impairment of PER1 is closely associated with the occurrence and progression of various diseases. In cardiovascular diseases, PER1 regulates blood pressure and renal function, and is involved in the anti-inflammatory mechanism of vascular injury. In the nervous system, PER1 regulates ischemic brain injury, sleep homeostasis, and associates with neurodegenerative diseases. In metabolic disorders, PER1 modulates endocrine function, glucose and lipid metabolism, as well as energy balance. In immune-related diseases, it regulates immune cell functions and inflammatory signaling pathways. In tumors, PER1 exerts tumor-suppressive effects and its low expression links to poor prognosis.
Cardiovascular diseases
PER1, a core component of the circadian clock system, is increasingly recognized as a key regulator of cardiovascular physiology and pathology. Its rhythmic expression in cardiovascular tissues (e.g., heart, blood vessels, and regulatory organs like the kidneys) integrates circadian rhythms with cardiovascular function, and its dysregulation contributes to the development and progression of various cardiovascular diseases (Table 1).
| Type of regulation | Related signaling molecules/pathways | Specific mechanisms | Evidence level | Cross-species conservation of mechanism | References |
|---|---|---|---|---|---|
| Blood Pressure, Sodium Metabolism, and Renal Function | ET-1 | Regulation of renal sodium handling and blood pressure rhythm through modulating the expression and activity of ET-1 may be involved in the regulation of hypertension progression via the RAAS | Preclinical evidence (animal model) | Partially conservative | (,) [37] [38] |
| MR | PER1 and MR may have a close regulatory relationship | Preclinical evidence (animal and cell models) | Conservative | (,,,) [24] [25] [39] [41] | |
| cAMP/PKA/CREB | GPR183 disrupts circadian rhythm signaling by inhibitingexpression and promotes endothelial senescence and dysfunction through the cAMP/PKA/CREB pathwayPER1 | Preclinical evidence (animal model) | Partially conservative | () [42] | |
| Orexin system genes | and orexin system genes exhibit coordinated regulation of their expression, which may influence the pathogenesis of sleep apnea syndromePER1 | Preclinical evidence (animal model) | Conservative pending verification | () [43] | |
| Anti-Inflammatory Mechanism of Vascular Injury | SIRT1 and other rhythmic genes | may be involved in activating SIRT1 and other rhythm-related genes, thereby enhancing antioxidant and anti-inflammatory capacitiesPER1 | Preclinical evidence (animal model) | Conservative pending verification | () [45] |
| IGF2 anti-inflammatory pathway | indirectly regulates the IGF2 anti-inflammatory pathway by maintaining normal SCN function or synergizing with other rhythmic genesPER1 | Preclinical evidence (animal model) | Conservative pending verification | () [46] | |
| VEGF pathway | The overexpression ofinhibits macrophage M1 polarization and the release of pro-inflammatory factors, as well as by activating the VEGF pathwayPER1 | Preclinical evidence (animal and cell model) | Partially conservative | () [47] |
Regulation of blood pressure, sodium metabolism, and renal function
The PER1 gene plays a critical role in regulating blood pressure, sodium metabolism, and renal function, particularly in salt-sensitive hypertension and renal injury. Studies have shown that Dahl salt-sensitive rats with PER1 gene knockout (KO) exhibit elevated blood pressure, increased renal expression of endothelin-1 (ET-1), and exacerbated renal damage (37, 38). In PER1−/− rats, plasma aldosterone levels and MR expression are elevated; specifically, KO of PER1 in distal nephrons and collecting ducts leads to increased aldosterone levels and enhanced renal Na+ retention (39). PER1 gene knockout displays significant sex-dependent differences across various animal models (e.g., mice and rats): male mice show a more pronounced response to KO of PER1, characterized by more severe hypertension and renal injury, whereas female mice remain unaffected (40).Mechanistically, PER1 influences renal sodium handling and blood pressure rhythms by regulating the expression and activity of ET-1, thereby antagonizing salt load-induced vascular contraction and fibrosis. This suggests that PER1 may be involved in the progression of hypertension by regulating the renin-angiotensin-aldosterone system (RAAS). Studies have shown that the interaction between PER1 and CK1 affects its phosphorylation and degradation, and CK1 regulates MR function by directly phosphorylating MR and indirectly phosphorylating MR co-regulators, implying a potential close regulatory relationship between PER1 and MR (24, 25, 41). Furthermore, studies have found that GPR183 disrupts circadian rhythm signaling by inhibiting PER1 expression, thereby promoting endothelial senescence and dysfunction through the cyclic 3’,5’-adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein (CREB) signaling pathway (42). In addition, in hypertension models, PER1 and the orexin system genes exhibit coordinated regulation of expression, which may influence the pathogenesis of sleep apnea syndrome (43).
Involvement in the anti-inflammatory mechanism of vascular injury
PER1 is involved in the anti-inflammatory mechanism of vascular ischemic injury. Liposomal prednisolone can induce the translocation of glucocorticoid (GC) receptors to the nucleus and upregulate the expression of PER1 mRNA, indicating that PER1 may participate in the anti-inflammatory mechanism of liposomal prednisolone in renal ischemia-reperfusion injury in rats (44). PER1 enhances myocardial tolerance to ischemia by maintaining circadian rhythms. In myocardial ischemia-reperfusion injury, KO of PER1 and PER2 genes impairs antioxidant and anti-inflammatory capacities, thereby exacerbating myocardial damage. The underlying mechanism is that PER1/PER2 double-knockout mice, due to circadian rhythm disruption, fail to activate rhythmic genes such as sirtuin 1 (SIRT1), leading to reduced antioxidant and anti-inflammatory capabilities (45). PER1 also contributes to the SCN-mediated cardioprotective mechanism. Studies have demonstrated that disruption of SCN function can induce the polarization of macrophages toward an anti-inflammatory phenotype by upregulating insulin-like growth factor 2 (IGF2), thereby improving cardiac repair after myocardial infarction. This mechanism may involve PER1 indirectly regulating the IGF2-mediated anti-inflammatory pathway through maintaining normal SCN function or synergizing with other rhythmic genes (46). In a mouse model of hindlimb ischemia (HLI), reduced expression of PER1 in skeletal muscle is associated with abnormal macrophage polarization (increased CD68) and decreased angiogenesis (reduced CD31). Overexpression of PER1 alleviates myocyte injury and promotes blood flow recovery via mechanisms involving the inhibition of macrophage M1 polarization and proinflammatory factor release, while activating the vascular endothelial growth factor (VEGF) pathway. This finding provides a novel therapeutic target for peripheral arterial disease (47).
Neurological disorders
PER1 exerts a pivotal role in neurological disorders, including ischemic brain injury, sleep homeostasis, and degenerative neuropathies, through multiple regulatory pathways such as circadian rhythm modulation, cell autophagy, oxidative stress, cellular apoptosis, and neurotransmitter systems (Table 2).
| Types of neurological diseases | Related signaling molecules/pathways | Specific mechanisms | Evidence level | Cross-species conservation of mechanism | References |
|---|---|---|---|---|---|
| Ischemic Brain Injury | Genetic variants of(rs2253820)PER1 | the rs225382 variant exacerbate the circadian rhythm of blood pressure | Preclinical evidence (animal model) | Conservative pending verification | () [48] |
| GluA1, p62 | Deletion ofdisrupts p62-mediated selective autophagic degradation of GluA1 and reduces autophagic activityPER1 | Preclinical evidence (animal model) | Conservative pending verification | () [49] | |
| Autophagy-related molecules (such as LC3, etc.) | deficiency disrupts the normal activity of the autophagic machinery (the basal LC3 levels were dramatically reduced with no changes in autophagic markers such as the LC3-II/LC3-I ratio)PER1 | Preclinical evidence (animal and cell models) | Partially conservative | (,) [50] [51] | |
| Sleep Homeostasis | CRY1 | Coordinated changes in the co-expression ofandplay a critical role in the disruption of sleep homeostasis after strokePER1CRY1 | Clinical evidence (cohort study) | Conservative | () [52] |
| Cortisol, melatonin | In rats with ischemic stroke,is associated with sleep-wake cycle disturbances, increased cortisol levels, and decreased melatonin secretionPER1 | Preclinical evidence (animal model) | Conservative | (,) [53] [54] | |
| PD | gene variants (e.g., loss-of-function, rs2225380 variants)PER1 | Loss-of-function variants ofare associated with motor dysfunctions in PD, such as dyskinesiaPER1 | Clinical evidence (cohort study) | Conservative pending verification | () [58] |
| The rs2225380 variant is positively correlated with PIGD subtype of sporadic PD | Clinical evidence (case-control study) | () [59] | |||
| Dopamine D2 receptor | Upregulation ofin the nucleus accumbens is associated with the activation of dopamine D2 receptorsPER1 | Preclinical evidence (animal model) | Conservative | (,) [60] [61] | |
| AD | gene polymorphism (rs3027178)PER1 | The G allele of rs3027178 confers a protective effect against AD | Clinical evidence (case-control study) | Conservative pending verification | () [63] |
| Autophagy-related molecules | KO ofaccelerates hippocampal aging in aged mice, which is related to impaired autophagy and excessive accumulation of misfolded proteinsPER1 | Preclinical evidence (animal model) | Conservative pending verification | () [65] | |
| Other neural functions | CREB | influences time-dependent memory formation by regulating the daytime phosphorylation of CREB in the hippocampusPER1 | Preclinical evidence (animal model) | Partially conservative | (,) [66] [67] |
| SYT14 | SYT14 deficiency leads to a significant upregulation ofin the hippocampus, accompanied by behavioral abnormalitiesPER1 | Preclinical evidence (animal model) | Conservative pending verification | () [68] | |
| Ion transport and apoptosis signal-related molecules | It may exacerbate neural damage by affecting ion transport and apoptotic signaling, and is associated with abnormal synaptic vesicles | Preclinical evidence (animal model) | Conservative pending verification | () [69] |
Maintaining autophagic activity in ischemic brain injury
In ischemic stroke, the enlargement of cerebral infarct volume has been associated with circadian rhythm disruption. Genetic variation at the rs2253820 locus of the PER1 gene has been shown to exacerbate the circadian rhythm of blood pressure (48). In a mouse model of cerebral ischemia, KO of PER1 eliminated the circadian variation in infarct volume, abolishing the protective effect observed during the active phase (nighttime). This was accompanied by impaired degradation of the glutamate ionotropic receptor AMPA type subunit 1 (GluA1) and reduced autophagic activity. In wild-type mice, ischemia during the active phase triggered sequestosome 1 (p62) - mediated selective autophagic degradation of GluA1 receptors, a process that was disrupted in the absence of PER1. These findings suggest that PER1 mitigates excitotoxicity by maintaining circadian regulation of autophagy-dependent GluA1 degradation (49). A study showed that levels of the proapoptotic factors cytochrome c (Cyt c) and apoptotic protease activating factor 1 (Apaf1) were higher in PER1−/− mice and basal LC3 levels were dramatically reduced. It is indicated that PER1 deficiency may slow down the autophagic machinery, increasing neuronal susceptibility to cerebral ischemia (50). Consistently with this, another study reported that hippocampal neurons from PER1−/− mice exhibited resistance to rapamycin-induced autophagy activation, as indicated by unchanged autophagic markers (e.g., LC3-II/LC3-I ratio), further underscoring the indispensable role of PER1 in maintaining basal autophagic activity (51).
Regulation of sleep homeostasis
Whereas inverse associations were observed with sleep latency, as well as α, β, and δ wave activities in the O1-A2 electrode derivation (52, 53). Moreover, coordinated changes in the co-expression of PER1 and CRY1 suggest that the core clock gene network plays a critical role in post-stroke sleep homeostasis disruption. In a rat model of ischemic stroke, pineal PER1 mRNA and protein levels were significantly elevated, particularly in aged rats, which correlated with sleep-wake cycle disturbances, increased cortisol levels, and decreased melatonin secretion (54). In clinical populations, reduced PER1 expression has been reported in individuals with chronic insomnia or those working night shifts, potentially linking circadian dysregulation to accelerated neurodegenerative processes, although the underlying mechanisms remain to be fully elucidated (55).
Association ofwith neurodegenerative diseases PER1
Genetic variants of PER1 have been directly linked to Parkinson’s disease (PD), particularly in the pathogenesis of motor dysfunctions (56, 57). Genetic analyses revealed significant enrichment of loss-of-function variants (e.g., missense mutations) in the PER1 gene among PD cohorts, which were associated with dyskinesia. A whole-exome sequencing study confirmed that PD patients carrying deleterious PER1 variants exhibited a higher incidence of dyskinesia, highlighting these variants as critical risk factors for PD-related motor symptoms (58). Gu et al. reported a significant association between clock genes and sporadic PD in the Chinese population, with the PER1 variant rs2253820 showing a stronger positive correlation in postural instability and gait disorder (PIGD) subtypes (59). These findings underscore PER1 as a susceptibility gene for PD.
Mechanistically, the variants of PER1 may disrupt dopamine signaling or circadian output pathways, leading to neuronal dysfunction and progressive degeneration. This is supported by animal studies demonstrating that PER1 upregulation in the nucleus accumbens is associated with dopamine D2 receptor activation, potentially modulating neurotransmitter release and influencing alcohol addiction behaviors (60, 61). Furthermore, PER1 genotypes (e.g., AG carriers of the risk allele G) have been associated with depressive states and altered white matter integrity, which may manifest as comorbid symptoms in neurodegenerative diseases such as Alzheimer’s disease (AD). Brain imaging data showed that AG carriers had a higher prevalence of depression and microstructural damage in white matter regions such as the corpus callosum compared to AA homozygotes (62). These results suggest that PER1 may contribute to the symptomatology of neurodegenerative diseases by regulating emotion-related signaling pathways (e.g., dopamine or glutamate systems).
PER1 influences AD risk through genetic polymorphisms and plays a critical role in hippocampal aging and AD pathology by regulating glial function, amyloid metabolism, and autophagic pathways. A significant association was identified between the rs3027178 polymorphism in the PER1 circadian gene and AD risk, with the G allele conferring a protective effect (63). Additionally, KO of PER1 accelerates age-related hippocampal changes in 24-month-old mice, including microglial morphological alterations, Aβ and lipofuscin deposition, and presenilin overexpression. These alterations are attributed to impaired autophagy and excessive accumulation of misfolded proteins in the hippocampus, thereby increasing neuronal vulnerability (64, 65).
In degenerative diseases, changes in PER1 expression are not only associated with specific disorders but also broadly involved in regulating behavior, memory, and neural functions. PER1 modulates time-dependent memory formation by gating the phosphorylation of CREB in the hippocampus (activated exclusively during the daytime), thereby linking circadian rhythms to learning efficiency (66, 67). Studies have shown that synaptotagmin 14 (SYT14) gene deficiency leads to a significant upregulation of PER1 expression in the hippocampus, accompanied by behavioral alterations (e.g., hyperactivity), which are related to dysregulated neural signaling pathways. PER1 may exacerbate neural damage by affecting ion transport and apoptotic signaling; ultrastructural studies further confirmed abnormal vesicle counts, suggesting an impact of PER1 on synaptic function (68). This mechanism is particularly crucial in degenerative diseases, as neurodegenerative disorders often involve protein homeostasis imbalance and mitochondrial dysfunction (69).
Endocrine and metabolic diseases
PER1 functions as a critical integrator of circadian rhythms and metabolic/endocrine signals, regulating glucose and lipid homeostasis, maintenance of energy balance, reproductive endocrine balance, and trace element metabolism (Table 3).
| Type of regulation | Role ofPER1 | Specific mechanisms | Evidence level | Cross-species conservation of mechanism | References |
|---|---|---|---|---|---|
| Lipid Metabolism | Upregulate the expression of target genes | Overexpression can upregulate the expression of PPARγ and its target genes, and promote the expression of adipogenic genes (including Srebp1c) | Preclinical evidence (animal model) | Conservative | (,) [70] [71] |
| Influence hepatic lipid accumulation | KO can reduce hepatic lipid accumulation and protect mice from ethanol-induced liver injury | Preclinical evidence (animal model) | Conservative pending verification | () [70] | |
| Interact with hepatic enzymes and regulate bile acid synthesis | It directly interacts with key hepatic enzymes involved in bile acid synthesis and participates in the rhythmic biosynthesis of bile acids via the PER1/PKA-mediated phosphorylation pathway | Preclinical evidence (animal model) | Conservative pending verification | () [72] | |
| Respond to stress stimuli | Fasting and high-fat stress can enhanceexpression, thereby increasing fat absorption and accumulationPER1 | Preclinical evidence (animal model) | Conservative pending verification | () [72] | |
| Association with serum indices | Serum triglyceride concentration is negatively correlated withmRNA levels (and positively correlated withmRNA levels)PER1CLOCK | Preclinical evidence (animal model) | Conservative pending verification | () [73] | |
| Glucose Metabolism | Affect glucose absorption | It regulates the transcription of SGLT1 by modulating the activity of E-box elements in the SGLT1 promoter | Preclinical evidence (animal and cell model) | Partially conservative | () [74] |
| Correlation with insulin resistance | Downregulation ofmay induce and exacerbates insulin resistancePER1 | Preclinical evidence (animal model) | Partially conservative | (,) [75] [76] | |
| Impact hepatic circadian clocks | The rhythmic expression ofin the liver and pancreas affects glucose homeostasisPER1 | Preclinical evidence (animal model) | Partially conservative | (,) [77] [78] | |
| Mutual regulation with blood glucose | Hyperglycemia can disrupt the rhythmic expression ofin the liver and olfactory bulb, while glucose restriction induces the expression of the circadian clock genevia the AMPK-SIRT1 pathwayPER1PER1 | Preclinical evidence (animal model) | Conservative pending verification | (,) [79] [80] | |
| Energy Balance | Regulate feeding behavior and energy expenditure | Phosphorylation of PER1 may determine feeding rhythms | Preclinical evidence (animal model) | Conservative pending verification | () [81] |
| The selective induction of hepaticduring fasting is a crucial mechanism by which hepatocytes integrate internal circadian rhythms and external nutritional signalsPER1 | Preclinical evidence (animal model) | Conservative pending verification | (,,) [28] [82] [83] | ||
| Endocrine and Copper Metabolism | Regulate PCOS | mediates ferroptosis and lipid metabolism by inhibiting the SREBF2/ALOX15 signaling pathwayPER1 | Preclinical evidence (animal model) | Conservative pending verification | (), [84] |
| Decreased expression ofandcan induce hyperandrogenism in ratsPER1PER2 | Clinical evidence (case-control study) and preclinical evidence (animal and cell models) | Conservative | () [85] | ||
| Modulate copper metabolism | Overexpression can alleviate nephrotoxicity by upregulating Atox1 | Preclinical evidence (animal model) | Conservative pending verification | () [86] | |
| Overexpression may exacerbate Cu-induced hepatotoxicity by downregulating Atp7b | Preclinical evidence (animal and cell models) | Conservative pending verification | () [87] |
Regulation of lipid metabolism
The PER1 gene can influence fat accumulation by regulating adipocyte differentiation and metabolism. Overexpression of PER1 upregulates the expression of peroxisome proliferator-activated receptor - gamma (PPAR-γ) and its target genes, while PER1 deletion protects mice from ethanol-induced liver injury by reducing hepatic lipid accumulation (70). PER1 promotes the expression of adipogenic genes (including sterol regulatory element-binding protein 1c), thereby enhancing lipid synthesis (71). Similarly, studies by GE et al. revealed that PER1 directly interacts with key hepatic enzymes involved in bile acid synthesis, such as cholesterol 7α-hydroxylase and sterol 12α-hydroxylase. The rhythmic biosynthesis of bile acids is associated with the activity and instability of bile acid synthases via the PER1/PKA-mediated phosphorylation pathway. Both fasting and high-fat stress can enhance PER1 expression, thereby increasing fat absorption and accumulation (72). Research has also found that serum triglyceride concentrations are positively correlated with CLOCK mRNA levels but negatively correlated with CRY2 and PER1 mRNA levels (73). These studies indicate that PER1 acts as an energy regulator, controlling daily fat absorption and accumulation.
Regulation of glucose metabolism
PER1 can affect glucose homeostasis by regulating insulin secretion and glucose uptake. It modulates the transcription of the sodium-glucose cotransporter 1 (SGLT1)—a glucose transporter—by regulating the activity of E-box elements in the SGLT1 promoter, thereby influencing glucose absorption (74). YAMAOKA et al. demonstrated that cold exposure in adipose tissue inhibits PER1 expression, and downregulation of PER1 may induce insulin resistance by impairing insulin signaling pathways (75). Xu et al. found that deletion of PER1 and PER2 exacerbates diet-induced insulin resistance and glucose intolerance, accompanied by aggravated hepatic inflammatory responses and metabolic dysregulation (76). FIGUEROA et al. reported that taurine improves obesity and diabetes by restoring the rhythmic expression of PER1 in pancreatic β-cells, suggesting that PER1 may serve as a potential target for taurine-based therapies in obesity and diabetes (77). Increased nuclear expression of PER1 can disrupt hepatic circadian clocks, further exacerbating glucose homeostasis imbalance (78). While PER1 influences blood glucose levels, blood glucose itself can regulate PER1 expression in tissues: hyperglycemia can disrupt the rhythmic expression of PER1 in the liver and olfactory bulb, leading to behavioral abnormalities (79), whereas glucose restriction induces the expression of the circadian clock gene PER1 via the AMP-activated protein kinase (AMPK) - SIRT1 pathway (80).
Maintenance of energy balance
The PER1 gene is also involved in regulating the body’s energy balance. Through interactions with the circadian clock system, it influences multiple aspects such as basal metabolic rate, food intake, and energy expenditure. Studies have shown that phosphorylation of PER1 determines feeding rhythms in mice, and S714 in hPER1 is a key site driving the rhythm of food intake behavior, playing a critical role in the physiological optimization of feeding behavior and energy consumption (81). Additionally, research indicates that time-restricted feeding may improve metabolic function in obese adult mice by reducing the circadian clock genes PER1 and PER2 in the liver. The underlying mechanism may involve the selective induction of hepatic PER1 during fasting; mice lacking hepatic PER1 fail to initiate autophagic flux, ketogenesis, and lipid accumulation. This suggests that the induction of PER1 may be an important mechanism by which hepatocytes integrate internal circadian rhythms and external nutritional signals to promote the appropriate utilization of calories (28, 82, 83).
Regulation of endocrine and copper metabolism
A study suggested that PER1 promotes ferroptosis and dysfunctional lipid metabolism in granulosa cells in polycystic ovary syndrome (PCOS) by inhibiting sterol regulatory element-binding factor 2 (SREBF2)/arachidonate 15-lipoxygenase (ALOX15) signaling pathway (84). However, another study revealed that decreased PER1 and PER2 promoted androgen excess via insulin-like growth factor-binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) in the liver (85).
In addition, overexpression of PER1 can reduce intracellular copper accumulation and alleviate nephrotoxicity by upregulating the copper chaperone protein antioxidant 1 copper chaperone (Atox1) (86). However, one study has found that the overexpression of PER1 may exacerbate Cu-induced hepatotoxicity by downregulating Cu transporter Atp7b in Hepa1–6 cells (87). We hypothesize that PER1 may exert distinct regulatory effects on copper metabolism across different tissues.
Immune and inflammatory-related diseases
PER1 regulates immune cell functions, inflammatory factor expression, and signaling pathways, thereby playing a critical role in immune and inflammatory responses (Table 4), with significant implications particularly in the pathogenesis of inflammatory bowel disease and allergic airway inflammation.
| Regulatory category | Cell type | Related signaling molecules/pathways | Specific mechanisms | Evidence level | Cross-species conservation of mechanism | References |
|---|---|---|---|---|---|---|
| Regulation of the function of immune cells | Naive CD4T lymphocytes+ | mTORC1 | Regulation ofexpression inhibits mTORC1 and suppresses Th1 polarization through adrenergic and glucocorticoid stress signaling pathwaysPER1 | Preclinical evidence (cell model) | Conservative pending verification | () [88] |
| Splenic lymphocytes | Ferroptosis | KO of bothand2 genes induces ferroptosis, leading to a decrease in immune cell counts, architectural damage of lymphoid tissues, and compromised immune functionPER1PER | Preclinical evidence (animal model) | Conservative pending verification | () [89] | |
| Treg Cell | COX7C | Decreasedexpression and impaired immunosuppression during circadian disruption exacerbate autoimmune diseases (e.g. uveitis)PER1 | Clinical evidence (case-control study) and preclinical evidence (animal and cell models) | Conservative | () [90] | |
| NK Cell | IFN-γ, Perforin,Granzyme B | Regulates NK cell rhythms and mediates circadian expression of IFN-γ, perforin and granzyme B | Preclinical evidence (animal model) | Conservative pending verification | () [91] | |
| Macrophage | TNF-α,PPAR-γ,Ccr2,IL-1β,IL-6,CCL2 | Inhibits M1 polarization and promotes M2 polarization;/mutations increase macrophage pro-inflammatory activation; interacts with PPAR-γ to reduce hepatic macrophage recruitment; inhibits inflammatory signaling pathways and enhances cellular reprogrammingPER1PER2 | Preclinical evidence (animal and cell models) | Partially conservative | (,,,) [47] [76] [92] [93] | |
| B Cell | - | The expression dynamics ofreporter gene increased dramatically during the transitional period of B cell developmentPER1Venus | Preclinical evidence (animal model) | Conservative pending verification | () [94] | |
| Regulation of inflammatory signaling pathways | Serum and liver | PPAR-γ, Ccr2, TNF-α, IL-1β, IL-6, CCL2 | may enhance PPAR-γ-mediated transcriptional repression of Ccr2 and reduce inflammatory factor expressionPER1 | Preclinical evidence (animal and cell models) | Partially conservative | () [92] |
| IL-1β-induced mandibular condylar chondrocytes | IL-1β, NF-κB, MMP13 | Regulation of IL-1β-induced MMP13 expression through the NF-κB pathway | Preclinical evidence (animal and cell models) | Conservative pending verification | () [95] | |
| Spinal cord astrocytes | p38, JNK1, NF-κB, CCL2, IL-6 | Regulation of CCL2 and IL-6 production via activation of the p38, JNK1, and NF-κB signaling pathways | Preclinical evidence (cell model) | Conservative pending verification | () [96] |
Regulation of immune cell functions
In T cells, the stress signaling pathways mediated by adrenergic and glucocorticoid hormones inhibit mTORC1 in naive CD4+ T cells by regulating the expression of the circadian rhythm gene PER1, thereby suppressing Th1 polarization (88). Double KO of PER1 and PER2 induces ferroptosis in splenic lymphocytes, leading to a reduction in the number of splenic immune cells, structural damage, and impairment of immune function (89). Circadian clock disturbances impair the stability and function of Treg cells through PER1-related cytochrome c oxidase subunit 7C (COX7C) - dependent mitochondrial metabolic processes, exacerbating diseases such as autoimmune uveitis (90), indicating that PER1 is a key factor in maintaining the stability and function of regulatory T (Treg) cells. PER1 plays an important regulatory role in the rhythm of natural killer (NK) cells and can mediate the circadian expression of interferon-gamma (IFN-γ), perforin, and granzyme B (91). Many studies have demonstrated a close association between PER1 and macrophages. Mutations in PER1 and PER2 disrupt circadian rhythms and boost macrophage inflammation (71). PER1 interacts with PPAR-γ to curb hepatic macrophage recruitment (92), shifts macrophage polarization from M1 to M2 (41), and reins in macrophage inflammatory signaling to spur cell reprogramming (93). In addition to the above immune cells, B cells are also regulated by clock elements. Dynamic regulation of PER1Venus levels has been observed during B cell development, with a sharp increase in reporter gene expression during the transitional phase (94).
Regulation of inflammatory signaling pathways
PER1 can also participate in autoimmune pathological processes by regulating inflammatory signaling pathways. Studies have found that inflammatory cytokines such as tumor necrosis factor - alpha (TNF-α), interleukin (IL) - 1β, IL-6, and chemokine (C-C motif) ligand 2 (CCL2) are increased in the serum and liver of PER1–/– mice. The underlying mechanism may be that PER1 interacts with PPAR-γ in the promoter region of the CC chemokine receptor 2 (Ccr2) gene, thereby enhancing PPAR-γ-mediated transcriptional inhibition of Ccr2 and attenuating excessive innate immune responses in endotoxin-induced liver injury (92). PER1 can regulate IL-1β-induced matrix metalloproteinase (MMP) 13 expression in mandibular condylar chondrocytes through the nuclear factor-kappa B (NF-κB) pathway (95). And PER1 can regulate the production of CCL2 and IL-6 through the activation of p38 mitogen-activated protein kinase (p38), c-Jun N-terminal kinase 1 (JNK1), and NF-κB in spinal astrocytes (96).
Participate in the pathogenesis of inflammatory diseases
Circadian clock genes (including PER1) are downregulated in intestinal tissues and peripheral blood mononuclear cells of patients with inflammatory bowel disease (IBD) (97). PER1 plays a critical role in maintaining intestinal barrier function. Studies have shown that intestinal mucosal barrier function is weakened in PER1/PER2 double-KO mice, accompanied by exacerbation of chronic colitis. Colon biopsy results reveal significantly upregulated wee1-like protein kinase (WEE1) mRNA levels and enhanced expression of cellular inhibitor of apoptosis protein 2 (cIAP2). The potential mechanism suggests that double-KO of PER1/PER2 triggers impaired cell division during proliferation via Wee1, leading to upregulation of anti-apoptotic pathways (98). In an ovalbumin-induced allergic airway inflammation model, PER1 protein expression is significantly upregulated in mouse lung tissues. PER1 may serve as a negative regulator of melatonin against Th2-type airway inflammation (99). Additionally, research has identified a functional PER1-like domain-containing protein 1 (PERLD1). PERLD1 haplotype can alter the sensitivity of peripheral blood mononuclear cells (PBMCs) through influencing soluble glycosylphosphatidylinositol anchor protein (sGPI-AP) levels, potentially contributing to individual susceptibility to allergic asthma (100).
Tumor
Low expression ofand its prognostic relevance PER1
PER1 is significantly downregulated in various malignant tumor tissues, including breast cancer, lung cancer, prostate cancer, and oral squamous cell carcinoma (101–103). The downregulation of PER1 is associated with poor prognosis: patients with high PER1 expression in gastric cancer exhibit prolonged survival (P = 0.0028) (104). In breast cancer tissues, high PER1 expression is correlated with longer overall survival and recurrence-free survival (HR: 0.78, 95% CI: 0.63–0.97) (105). In ovarian cancer, low PER1 expression is linked to reduced overall survival, particularly in early-stage (I+II) patients where low expression indicates poor prognosis (106).
Core mechanisms ofin tumor suppression PER1
PER1 plays an important role in various tumors, such as cholangiocarcinoma, glioma, oral squamous cell carcinoma, nasopharyngeal carcinoma, prostate cancer, and gastric cancer (Table 5). Its mechanisms involve cell proliferation, apoptosis, cell cycle progression, metabolism, immune regulation, etc.
| Type of tumor | Mechanism of action | Regulatory molecules/pathways | Evidence level | Cross-species conservation of mechanism | Reference |
|---|---|---|---|---|---|
| Cholangiocarcinoma | Overexpression inhibits cell proliferation via upregulating cell cycle regulators, with increased G2/M and S phase cells and reduced G1 phase cells | WEE1, CREB phosphatase 1, CRE-BP1 | Preclinical evidence (animal and cell model) | Conservative | () [114] |
| Glioma | may be attributable to enhanced CHK2-p53 signaling and proapoptotic processesPER1 | CHK2-p53 | Preclinical evidence (cell model) | Conservative pending verification | () [111] |
| OSCC | KO promotes cell growth, proliferation, anti-apoptosis, migration and invasion; it inhibits glycolysis-mediated cell proliferation | Ki-67, MDM2, BCL-2, MMP2, MMP9; C-MYC, p53, BAX, TIMP-2; PER1/RACK1/PI3K, PI3K/AKT | Preclinical evidence (animal and cell models) | Conservative | (,,,) [103] [116] [117] [119] |
| Nasopharyngeal Carcinoma | Overexpression reduces cell invasion and migration | - | Preclinical evidence (cell model) | Conservative pending verification | () [117] |
| Prostate Cancer | It interacts with AR, serving as a negative regulator of AR activity to maintain hormonal homeostasis | AR | Preclinical evidence (animal and cell models) | Conservative | () [101] |
| Breast Cancer | Downregulation ofin tumor cells increases tumor growth, but only at two specific times of the dayPER1 | - | Preclinical evidence (animal and cell models) | Conservative | () [110] |
| Promoter methylation of thecorrelates with c-erbB2 immunohistochemical reaction of > or = 2+ and has a strong inverse correlation with ER positivityPER1 | Clinical evidence | Partially conservative | () [108] | ||
| Trastuzumab-resistant Gastric Cancer Cells | It forms a complex with PPAR-γ, promotes the upregulation of HK2, and enhances glycolytic activity | PPAR-γ, HK2 | Preclinical evidence (animal and cell models) | Conservative | () [120] |
| Ovarian Cancer | Expression levels are associated with immune infiltration and involved in immune evasion | Neutrophils, Treg cells, and M2-type macrophages (their infiltration is positively correlated withexpression)PER1 | Clinical evidence (cohort study) | Conservative pending verification | () [106] |
| Endometrial Cancer | Overexpression promotes the expression of immune factors and the upregulation of immune checkpoints, and may inhibit tumor invasion by activating immune responses | TNF-α, IL-6, PD-1/PD-L1 | Clinical evidence (case-control study) and preclinical evidence (cell model) | Partially conservative | () [121] |
Regulation of cell proliferation, apoptosis and cell cycle progression
Abnormal expression of PER1 disrupts cell cycle progression, inhibits DNA damage repair, and affects tumor development by regulating cell proliferation and apoptosis. Studies have shown that PER1 overexpression sensitizes human cancer cells to DNA damage-induced apoptosis, whereas PER1 inhibition attenuates apoptosis in similarly treated cells (107, 108). Abnormal PER1 expression leads to dysregulation of multiple genes associated with cell cycle arrest and apoptosis, including Cyclin (CCN) B1, D, E, WEE1, cyclin-dependent kinase (CDK) 1, c-myc, tumor protein p53 (p53), and cyclin-dependent kinase inhibitor 1A (p21) (109–111). As a key regulator of DNA damage repair and cell cycle, p53 mediates PER1-dependent transcriptional regulation of WEE1 and CCNB1 (112, 113). In cholangiocarcinoma, PER1 overexpression suppresses cell proliferation by upregulating cell cycle regulators (e.g., WEE1, CREB phosphatase 1, CRE-BP1), increasing the proportion of G2/M and S phase cells, and reducing G1 phase cell populations (114). In glioma, PER1 may enhanced checkpoint kinase 2 (CHK2) - p53 signaling and proapoptotic processes and downregulation of PER1 decreases radiosensitivity and apoptosis in X-ray-irradiated U343 glioma cells (111). PER1 also regulates G1/S transition by modulating p21-mediated inhibition of CDK2/4/6 (113, 115), and sensitizes cancer cells to ionizing radiation-induced apoptosis via c-Myc-dependent suppression of p21-mediated cell cycle arrest (109). In oral squamous cell carcinoma, KO of PER1 promotes cell growth, proliferation, apoptosis resistance, migration and invasion, accompanied by upregulated mRNA expression of Ki-67, mouse double minute 2 homolog (MDM2), B-cell lymphoma 2 (BCL-2), MMP2, MMP9, and downregulated expression of cellular MYC proto-oncogene (C-MYC), p53, BCL-2 associated X protein (BAX), tissue inhibitor of metalloproteinases 2 (TIMP-2) (116). Additionally, PER1 overexpression reduces invasion and migration of nasopharyngeal carcinoma cells (117).
Suppression of metabolic reprogramming
In prostate cancer, PER1 interacts with the androgen receptor (AR), serving as a negative regulator of AR activity. Activated AR stimulates PER1 expression, which in turn attenuates AR signaling to maintain hormonal homeostasis (101). The methylation status of the PER1 promoter is negatively correlated with estrogen receptor (ER)-positive expression in breast cancer, suggesting that PER1 methylation variations may influence ER expression (118). In oral squamous cell carcinoma (OSCC), PER1 inhibits glycolysis-mediated cell proliferation by forming a PER1/receptor for activated C kinase 1 (RACK1)/phosphatidylinositol 3-kinase (PI3K) complex, regulating PI3K stability, and modulating PI3K/protein kinase B (AKT) signaling-dependent mechanisms (103, 119). In trastuzumab-resistant gastric cancer cells, PER1 complexes with PPAR-γ to promote upregulation of hexokinase 2 (HK2), thereby enhancing glycolytic activity (120).
Modulation of immune microenvironment
PER1 expression levels are associated with tumor immune infiltration, participating in immune evasion by influencing immune factor expression and immune cell recruitment. Studies have shown that PER1 expression in ovarian cancer is positively correlated with infiltration of neutrophils, Treg cells, and M2-type macrophages (106). Additionally, PER1 overexpression in endometrial cancer cells promotes the expression of immune factors TNF-α and IL-6, while upregulating immune checkpoints programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1). This may inhibit tumor invasion by activating immune responses (121).
Conclusions and prospects
As a core gene of the circadian clock, PER1 plays a critical role in the occurrence and development of various diseases through complex mechanisms and signaling pathways (Table 6). Its abnormal expression and functional disorders widely affect the physiological and pathological processes of the organism. Based on existing studies, the function of PER1 exhibits tissue specificity, but its mechanisms of action in different organs/diseases remain incompletely understood. Moreover, most current research is based on animal or cell models, but there are not many clinical studies on PER1 and large-scale clinical validation remains lacking (Table 7), especially in the development of gene therapy or targeted drugs. In-depth studies on the mechanisms of PER1 in different diseases provide new perspectives for understanding the pathogenesis of these diseases and lay a theoretical foundation for the development of therapeutic strategies based on circadian rhythm regulation.
Future research on PER1 is expected to achieve breakthroughs in the following aspects: First, to further clarify the specific regulatory mechanisms of PER1 in different tissues and cell types, particularly its dynamic changes during disease occurrence and progression. Second, to develop drugs or therapeutic approaches that can precisely target PER1 and its related signaling pathways, such as the development of drugs based on CK1 inhibitors or FMRP mimetics, to restore the normal function and rhythm of PER1. Third, to explore PER1 as a biomarker for disease diagnosis and prognosis assessment, enabling early disease diagnosis and personalized treatment by detecting PER1 expression levels, rhythm changes, etc. With the continuous in-depth study of PER1, it is believed that disease prevention and treatment strategies based on circadian rhythm regulation will bring new hope for improving human health.
| Disease field | Core signaling pathway | Interaction betweenand signaling pathwayPER1 | Related pathological manifestations | Evidence level | Cross-species conservation of mechanism | Reference |
|---|---|---|---|---|---|---|
| Cardiovascular Diseases | ET-1/RAAS | Regulates ET-1 expression and activity, influences renal sodium transport and blood pressure rhythm, antagonizes salt load-induced vascular contraction and fibrosis, and participates in hypertension progression via RAAS regulation | Hypertension, renal injury, vascular fibrosis | Preclinical evidence (animal model) | Partially conservative | (,) [37] [38] |
| MR | Maintains close regulatory relationship with MR; CK1-mediated phosphorylation of PER1 indirectly modulates MR function, affecting renal sodium retention and aldosterone levels | Salt-sensitive hypertension, renal sodium metabolism disorder | Preclinical evidence (animal and cell models) | Conservative | (,,,) [24] [25] [39] [41] | |
| cAMP/PKA/CREB pathway | Inhibited by GPR183, leading to disrupted circadian rhythm signals and promoted endothelial senescence and dysfunction through this pathway | Hypertension-related endothelial injury, vascular aging | Preclinical evidence (animal model) | Partially conservative | () [42] | |
| SIRT1 | Maintains circadian rhythm, activates SIRT1 and other rhythmic genes, enhances myocardial antioxidant and anti-inflammatory capacities to alleviate ischemia-reperfusion injury | Myocardial ischemia-reperfusion injury | Preclinical evidence (animal model) | Conservative pending verification | () [45] | |
| IGF2 anti-inflammatory pathway | Indirectly regulates IGF2-mediated anti-inflammatory pathway by maintaining normal SCN function or synergizing with other rhythmic genes, improving cardiac repair after myocardial infarction | Impaired cardiac repair after myocardial infarction, vascular inflammation | Preclinical evidence (animal model) | Conservative pending verification | () [46] | |
| VEGF pathway | Overexpression inhibits macrophage M1 polarization and proinflammatory cytokine release, activates VEGF pathway to promote blood flow recovery and alleviate limb ischemia injury | Peripheral arterial disease, tissue injury after limb ischemia | Preclinical evidence (animal and cell models) | Partially conservative | () [47] | |
| Neurological Disorders | GluA1/p62 autophagy pathway | Maintains p62-mediated selective autophagic degradation of GluA1;deficiency disrupts this process, causes GluA1 accumulation and reduced autophagic activity, exacerbating ischemic brain injuryPER1 | Ischemic brain injury, enlarged cerebral infarct volume | Preclinical evidence (animal model) | Conservative pending verification | () [49] |
| LC3 | Deficiency slows autophagic machinery (reduced basal LC3 levels, unchanged LC3-II/LC3-I ratio), increases neuronal susceptibility to cerebral ischemia | Ischemic brain injury, neuronal damage | Preclinical evidence (animal and cell models) | Partially conservative | (,) [50] [51] | |
| Cortisol/Melatonin | Abnormal expression causes sleep-wake cycle disorder, increased cortisol, and decreased melatonin secretion, leading to post-stroke sleep disturbance and chronic insomnia | Post-ischemic stroke sleep disorder, chronic insomnia | Preclinical evidence (animal model) | Conservative | (,) [53] [54] | |
| Dopamine D2 receptor | Upregulation in nucleus accumbens is associated with dopamine D2 receptor activation, affecting neurotransmitter release and participating in PD-related dyskinesia | PD-related dyskinesia | Preclinical evidence (animal model) | Conservative | (,) [60] [61] | |
| Metabolic & Endocrine Diseases | PPARγ/Srebp1c | Overexpression upregulates PPARγ and its target genes, promotes adipogenic gene (Srebp1c) expression and lipid synthesis; PER1 deletion reduces hepatic lipid accumulation and alleviates ethanol-induced liver injury | Abnormal lipid metabolism, hepatic lipid accumulation, non-alcoholic fatty liver | Preclinical evidence (animal model) | Conservative | (,) [70] [71] |
| PER1/PKA pathway | Directly interacts with key hepatic bile acid synthesis enzymes (e.g., cholesterol 7α-hydroxylase), participates in rhythmic bile acid biosynthesis via PKA-mediated phosphorylation; fasting/high-fat stress enhances PER1 expression to increase fat absorption | Bile acid metabolism disorder, abnormal fat absorption | Preclinical evidence (animal model) | Conservative pending verification | () [72] | |
| SGLT1 | Regulates E-box element activity in SGLT1 promoter, modulates SGLT1 transcription and glucose absorption, affecting glucose homeostasis | Glucose metabolism disorder, impaired blood glucose homeostasis | Preclinical evidence (animal and cell models) | Partially conservative | () [74] | |
| AMPK-SIRT1 pathway | Glucose restriction induces PER1 expression via this pathway; PER1 deficiency exacerbates diet-induced insulin resistance and glucose intolerance | Type 2 diabetes, insulin resistance, diet-induced glucose intolerance | Preclinical evidence (animal model) | Conservative pending verification | (,) [76] [80] | |
| SREBF2/ALOX15 pathway | Inhibits this pathway to promote granulosa cell ferroptosis and lipid metabolism disorder in PCOS | Polycystic Ovary Syndrome (PCOS), abnormal lipid metabolism | Preclinical evidence (animal model) | Conservative pending verification | () [84] | |
| IGFBP4/SHBG | Decreased PER1/PER2 expression promotes androgen excess via regulating IGFBP4 and SHBG in the liver | PCOS, hyperandrogenism | Clinical evidence (case-control study) + Preclinical evidence (animal and cell models) | Conservative | () [85] | |
| Atox1/Atp7b | Overexpression upregulates Atox1 to reduce intracellular copper accumulation and alleviate nephrotoxicity; overexpression may exacerbate Cu-induced hepatotoxicity by downregulating Atp7b in hepatocytes | Copper-induced nephrotoxicity, Cu-induced hepatic toxicity | Preclinical evidence (animal and cell models) | Conservative pending verification | (,) [86] [87] | |
| Immune & Inflammatory Diseases | mTORC1 pathway | Regulated by adrenergic and glucocorticoid stress signaling; PER1 expression inhibits mTORC1 activity and suppresses Th1 polarization to maintain immune homeostasis | Autoimmune diseases, T-cell subset imbalance | Preclinical evidence (cell model) | Conservative pending verification | () [88] |
| Ferroptosis pathway | PER1/PER2 double knockout induces ferroptosis in splenic lymphocytes, leading to reduced immune cell counts, lymphoid tissue structural damage, and impaired immune function | Immune deficiency, lymphoid tissue structural damage | Preclinical evidence (animal model) | Conservative pending verification | () [89] | |
| COX7C | Maintains Treg cell stability and function via COX7C-dependent mitochondrial metabolism; decreased PER1 expression impairs Treg immunosuppressive function | Autoimmune uveitis | Clinical evidence (case-control study) + Preclinical evidence (animal and cell models) | Conservative | () [90] | |
| NF-κB pathway | Regulates IL-1β-induced MMP13 expression in mandibular condylar chondrocytes; activates NF-κB pathway to promote CCL2/IL-6 production in spinal astrocytes | Temporomandibular joint osteoarthritis, spinal inflammation, intestinal barrier injury | Preclinical evidence (animal and cell models) | Conservative pending verification | (,,) [95] [96] [98] | |
| PERLD1/sGPI-AP | PERLD1 haplotype alters PBMC sensitivity by influencing sGPI-AP levels, contributing to individual susceptibility to allergic asthma | Allergic asthma | Clinical evidence (case-control study) | Conservative | () [100] | |
| Tumors | p53/WEE1/CCNB1 pathway | Regulates p53-mediated transcription of WEE1 and CCNB1, affects cell cycle G2/M progression and DNA damage repair, enhances cancer cell sensitivity to DNA damage-induced apoptosis | Cholangiocarcinoma, glioma, multiple tumor proliferation, radiotherapy resistance | Preclinical evidence (animal and cell models) | Conservative | (,,) [109] [111] [114] |
| PER1/RACK1/PI3K pathway | Forms complex with RACK1 to regulate PI3K stability, inhibits PI3K/AKT-mediated glycolysis, suppresses proliferation and invasion of oral squamous cell carcinoma (OSCC) | OSCC proliferation and invasion | Preclinical evidence (animal and cell models) | Conservative | (,) [103] [119] | |
| AR | Interacts with androgen receptor (AR) as a negative regulator of AR activity, maintains hormonal homeostasis, inhibits prostate cancer progression | Prostate cancer progression | Preclinical evidence (animal and cell models) | Conservative | () [101] | |
| PPAR-γ/HK2 | Forms complex with PPAR-γ to promote HK2 upregulation, enhances glycolytic activity, participates in the development of trastuzumab-resistant gastric cancer | Trastuzumab-resistant gastric cancer, tumor metabolic reprogramming | Preclinical evidence (animal and cell models) | Conservative | () [120] | |
| PD-1/PD-L1 | Overexpression promotes TNF-α/IL-6 expression and PD-1/PD-L1 upregulation, activates anti-tumor immune responses, inhibits endometrial cancer invasion and immune escape | Endometrial cancer invasion, tumor immune escape | Clinical evidence (case-control study) + Preclinical evidence (cell model) | Partially conservative | () [121] |
| Types of diseases | Related signaling molecules/pathways | Specific functions/mechanisms | Evidence level | Cross-species conservation of mechanism | References |
|---|---|---|---|---|---|
| PD | gene variants (e.g.,loss-of-function, rs2225380 variants)PER1 | Loss-of-function variants ofare associated with motor dysfunctions in PD, such as dyskinesiaPER1 | IIb | Conservative pending verification | () [58] |
| The rs2225380 variant is positively correlated with PIGD subtype of sporadic PD | IIIa | () [59] | |||
| AD | gene polymorphism (rs3027178)PER1 | The G allele of rs3027178 confers a protective effect against AD | IIIa | Conservative pending verification | () [63] |
| PCOS | IGFBP4, SHBG | Decreasedandexpression can result in excessive androgen productionPER1PER2 | IIIa | Conservative | () [85] |
| Uveitis | COX7C | High Tregs of COX7C were positively correlated with the severity of uveitis | IIIa | Conservative | () [90] |
| IBD | – | expression was significantly downregulated in intestinal tissues and PBMCs in IBD patientsPER1 | IIb | Conservative | () [97] |
| Allergic asthma | sGPI-AP | PERLD1 haplotype alters the sensitivity of PBMCs through influencing sGPI-AP levels, | IIIa | Conservative | |
| OSCC | – | Per1 expression is significantly downregulated in OSCC | IIIa | Conservative | () [103] |
Glossary
Funding Statement
The author(s) declare financial support was received for the research and/or publication of this article. This research was supported by the Hunan Provincial Health Commission Health Research Project (Grant No. 202204124873) and the Hunan Provincial Natural Science Foundation (Grant No. 2025JJ80143).
Footnotes
Author contributions
YZ: Writing – original draft. YL: Writing – review & editing. TL: Writing – review & editing. XH: Writing – review & editing. KC: Writing – review & editing. LT: Conceptualization, Writing – review & editing. LG: Conceptualization, Writing – review & editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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