AMPK/SIRT1/PGC‐1α Signaling Pathway: Molecular Mechanisms and Targeted Strategies From Energy Homeostasis Regulation to Disease Therapy

AMPK functions as a heterotrimeric complex composed of α, β, and γ subunits, each contributing distinct structural and functional roles. The catalytic α subunit houses the kinase domain responsible for substrate phosphorylation, while the β subunit mediates complex assembly. The γ subunit contains four tandem cystathionine β‐synthase (CBS) domains that function as energy‐sensing modules by binding AMP, ADP, and ATP [5]. This molecular architecture enables precise kinase activity regulation through dual mechanisms. Under energy‐depleted conditions (characterized by elevated AMP/ADP and reduced ATP), AMP/ADP binding to the γ subunit induces allosteric changes that expose the kinase active site; conversely, ATP competitively binds to the CBS domains during nutrient‐replete conditions, effectively suppressing kinase activation and preventing unnecessary energy expenditure [20]. AMPK activation requires phosphorylation at Thr172 on its α subunit, a tightly regulated process mediated by distinct upstream kinases responding to different stimuli. Under metabolic stress, LKB1 phosphorylates AMPK during energy deprivation [21]. Calcium signaling triggers activation through CaMKKβ when intracellular Ca²⁺ levels rise. Cysteine dioxygenase type 1 (Cdo1) enhances this process by bridging CaMKK2 to AMPK [22, 23]. During inflammatory or oxidative stress, TGFβ‐activated kinase 1 (TAK1) mediates phosphorylation [24]. This multilayered regulatory system allows AMPK to integrate diverse cellular stress signals, precisely control downstream metabolic pathways, and maintain sensitive energy homeostasis.

AMPK's functional states are dynamically regulated through a sophisticated network of post‐translational modifications (PTMs) that extend beyond its canonical Thr172 phosphorylation. Multiple phosphorylation sites enable precise regulatory control. AKT‐mediated phosphorylation at α‐Ser485/491 suppresses AMPK activity, whereas β‐Ser108 autophosphorylation enhances kinase function. Additionally, AMPK‐dependent phosphorylation of GSDME at Thr6 inhibits pyroptosis [25, 26, 27]. Acetylation modifications also play a key role, with SIRT1 activating AMPK through α subunit deacetylation [28]. Additionally, ubiquitin‐dependent regulation occurs through MG53‐mediated degradation of AMPKα in response to glucose levels [29]. This intricate PTM network reveals that AMPK activity integrates not just energy status but also coordinated covalent modifications, creating multiple potential intervention points for therapeutic targeting. The system's complexity offers diverse opportunities for pharmacological manipulation of AMPK in drug development.

AMPK activity is subject to sophisticated allosteric regulation by small‐molecule compounds and therapeutic agents, forming an integrated pharmacological control network. The direct AMPK activators MK‐8722 and MT 63–78 both bind to an allosteric site on the β subunit to induce conformational activation [30]. Similar to AMP, MT 63–78 can also inhibit protein phosphatase 2Cα from dephosphorylating the AMPK Thr172 site, thereby maintaining the phosphorylated state of AMPK [31]. Similarly, 5‐aminoimidazole‐4‐carboxamide riboside (AICAR) undergoes intracellular conversion to ZMP, an AMP mimetic that triggers AMPK activation through structural mimicry of AMP's allosteric effects [32, 33]. In contrast, dorsomorphin competitively inhibits AMPK by reversibly binding to the catalytic domain, effectively blocking AICAR‐induced phosphorylation [34]. Beyond direct modulators, AMPK can be activated indirectly by compounds that elevate cellular AMP levels or calcium concentrations, exemplified by metformin's inhibition of mitochondrial complex I leading to AMP/ADP accumulation and subsequent AMPK activation [35, 36]. These interconnected regulatory mechanisms collectively influence diverse cellular processes including metabolism, growth, autophagy, and inflammatory responses, demonstrating AMPK's central role as a metabolic sensor integrating multiple pharmacological inputs.

As the primary cellular energy sensor, AMPK orchestrates a multifaceted metabolic network to maintain energy equilibrium. In glucose metabolism, AMPK enhances cellular glucose uptake by facilitating GLUT4 translocation to the plasma membrane and simultaneously activating rate‐limiting glycolytic enzymes such as phosphofructokinase‐1 [37]. This regulatory mechanism is particularly crucial in skeletal muscle, where AMPK mediates exercise‐induced GLUT4 membrane translocation, synergizing with insulin signaling to regulate glucose internalization [38]. Concurrently, AMPK potently suppresses hepatic gluconeogenesis through inhibition of the transcriptional coactivator CRTC2 [39]. Notably, impaired AMPK activity in type 2 diabetes mellitus (T2DM) patients contributes to defective glucose uptake and fatty acid oxidation, resulting in hyperglycemia [1], positioning AMPK activation as a promising therapeutic strategy for T2DM via mitochondrial function improvement.

In lipid metabolism, AMPK exerts inhibitory control over fatty acid synthesis through phosphorylation‐mediated inactivation of acetyl‐CoA carboxylase (ACC), thereby preventing excessive lipid accumulation [40]. In the regulation of proteostasis and autophagy, AMPK displays bifunctional control. On one hand, it maintains energy balance by suppressing mTORC1‐dependent translational processes under nutrient stress [41]. On the other hand, it directly stimulates autophagic flux via targeted phosphorylation of core autophagy regulators including ULK1 and BECN1 [42]. Furthermore, AMPK maintains mitochondrial integrity by coordinating mitochondrial biogenesis, dynamics (fusion/fission), and mitophagy [43, 44]. Collectively, AMPK serves as a metabolic guardian through its coordinated regulation of four fundamental processes, including glucose uptake enhancement, lipid metabolism suppression, autophagy initiation, and mitochondrial optimization. This integrated regulatory network not only preserves cellular energy homeostasis but also establishes AMPK as a natural defense hub against metabolic disorders such as T2DM.

Alzheimer's disease (AD) presents three defining pathological hallmarks including β‐amyloid (Aβ) plaque accumulation, neurofibrillary tangles formed by hyperphosphorylated Tau protein, and progressive neuronal loss with synaptic dysfunction. The AMPK/SIRT1/PGC‐1α pathway demonstrates therapeutic potential by operating through three complementary mechanisms [82]. In Aβ metabolism regulation, AMPK activation suppresses BACE1/γ‐secretase expression, inhibiting aberrant cleavage of amyloid precursor protein (APP) and reducing Aβ production [83], while the AMPK‐ULK1 axis enhances autophagic flux to promote Aβ lysosomal degradation [84], and PGC‐1α boosts microglial phagocytic capacity for accelerated Aβ clearance [83, 85] (Table 1). For tau pathology modulation, SIRT1‐mediated Tau deacetylation effectively prevents its hyperphosphorylation and subsequent neurofibrillary tangle formation [86, 87]. Regarding neuroimmune regulation and mitochondrial restoration, the pathway drives microglial polarization from pro‐inflammatory (M1) to anti‐inflammatory (M2) phenotypes, reducing neurotoxic cytokine release while enhancing cellular antioxidant defenses [88], and PGC‐1α‐mediated mitochondrial biogenesis restores synaptic plasticity by improving energy metabolism [89]. This innovative therapeutic strategy achieves comprehensive intervention by concurrently addressing Aβ clearance, Tau pathology, neuroimmune modulation, and mitochondrial restoration, thereby overcoming the constraints of traditional single‐target approaches in Alzheimer's disease. The AMPK/SIRT1/PGC‐1α axis therefore emerges as a transformative platform for developing disease‐modifying therapies.

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra, accumulation of α‐synuclein aggregates (Lewy bodies), and gliosis, with pathogenesis involving complex interactions among mitochondrial dysfunction, oxidative stress, protein homeostasis disruption, and neuroinflammation [90, 91]. The AMPK/SIRT1/PGC‐1α pathway plays a central role in this process, and its dysregulation contributes to PD progression. PD involves AMPK dysfunction characterized by reduced AMPK phosphorylation in the substantia nigra, impairing cellular stress responses, where AMPK activation exerts neuroprotection through direct phosphorylation of ULK1 and mTORC1 inhibition to enhance autophagy, along with TFEB activation to promote lysosomal biogenesis, facilitating α‐synuclein clearance and improving neuronal survival in MPTP models [92, 93, 94, 95]. SIRT1 suppression in PD leads to downregulated SIRT1 expression, resulting in impaired autophagy and protein aggregation, mitochondrial dysfunction with increased ROS production, and apoptotic pathway activation, while SIRT1 overexpression rescues mitochondrial function and reduces neuronal apoptosis [96, 97]. Additionally, PGC‐1α deficiency contributes to mitochondrial failure, as reduced PGC‐1α expression decreases mitochondrial biogenesis and lowers ATP synthesis, whereas PGC‐1α activation restores respiratory chain function by upregulating NRF1/TFAM, ameliorating motor deficits [93, 98]. Collectively, the AMPK/SIRT1/PGC‐1α axis integrates energy sensing (AMPK), proteostasis (SIRT1), and mitochondrial function (PGC‐1α), forming a core neuroprotective mechanism in PD. Targeted modulation of this pathway offers a promising strategy to counteract dopaminergic neurodegeneration.

Recent research has revealed two promising therapeutic strategies for Parkinson's disease targeting the AMPK/SIRT1/PGC‐1α pathway. First, TPP‐modified macrophage membrane‐coated Cu₂₋ₓSe‐curcumin nanoparticles (CSCCT) selectively activate SIRT1/PGC‐1α signaling in degenerating neurons, promoting mitochondrial biogenesis with demonstrated improvements in complex I activity and motor function [99]. Second, peptide agonist teaghrelin simultaneously activates both AMPK/SIRT1/PGC‐1α and ERK1/2 pathways, effectively protecting against MPP⁺‐induced neuronal apoptosis and enhancing neuronal survival [92]. These interventions exert neuroprotection through three synergistic mechanisms, including the enhanced lysosomal degradation of α‐synuclein aggregates, the suppression of ROS generation via SOD2 activation, and the restoration of mitochondrial respiratory function through increased ATP production (Table 1). These findings establish that targeted activation of the AMPK/SIRT1/PGC‐1α pathway represents a novel multidimensional therapeutic paradigm for PD, simultaneously addressing protein homeostasis maintenance, oxidative stress mitigation, and mitochondrial functional recovery.

Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration leading to muscle atrophy [100, 101, 102], with pathogenesis involving mitochondrial accumulation of mutant SOD1 protein [103], glutamate excitotoxicity‐induced Ca²⁺ overload and mitochondrial ROS burst [104], as well as protein homeostasis disruption and neuroinflammatory cascades [105, 106], where the AMPK/SIRT1/PGC‐1α pathway plays a dynamic regulatory role (Table 1). Despite paradoxical AMPK hyperactivation in ALS models, its phosphorylation levels are significantly reduced [107], with appropriate AMPK activation exerting neuroprotective effects through induction of autophagy to clear mutant proteins (reduced SOD1 aggregates) [108], phosphorylation of mTOR negative regulators to inhibit mTORC1 signaling and subsequent protein translation [109], and promotion of mitochondrial biogenesis and fatty acid metabolism to potentially slow disease progression [110]. The SIRT1 regulatory network influences cellular aging processes and modulates stress/inflammatory responses in neurodegeneration [111], exerting protective effects in ALS through FOXO/PGC‐1α deacetylation to enhance antioxidant capacity (increased SOD2 activity) and activation of autophagy pathways for misfolded protein clearance (improved aggregate removal) [112, 113], with SIRT1 overexpression shown to mitigate SOD1 mutation‐induced ALS pathology [112]. Given PGC‐1α's reduced expression in ALS patient muscle tissue [114], its activation demonstrates therapeutic potential by enhancing mitochondrial biogenesis (improved respiratory chain complex activity), reducing ROS toxicity (decreased superoxide levels), and modulating neuromuscular junction gene expression [115, 116]. The AMPK/SIRT1/PGC‐1α axis thus provides a multidimensional intervention strategy targeting core ALS pathologies including mutant protein clearance (SOD1 aggregates), oxidative damage control (ROS burst), and mitochondrial reprogramming (respiratory chain repair/neuromuscular junction maintenance), with these findings not only revealing a reversible window for motor neuron degeneration but also establishing the molecular foundation for a "neuro‐metabolic homeostasis remodeling" therapeutic paradigm in ALS treatment.

Diabetes mellitus presents two fundamental pathological characteristics including insulin resistance and β‐cell dysfunction [117, 118, 119]. The AMPK/SIRT1/PGC‐1α pathway forms a coordinated regulatory network that improves metabolic disorders through multiple mechanisms. AMPK activation boosts glucose uptake in skeletal muscle by promoting GLUT4 movement [120, 121] and reduces liver fat production while increasing fat breakdown through CPT1 activation [122] (Table 1). Drug‐induced AMPK activation shows a significant improvement in blood sugar control and insulin response in obese animal models [123]. SIRT1 provides organ protection by modifying FOXO1/PGC‐1α to strengthen antioxidant defenses [124], relieving nerve damage in diabetes [125], and reducing kidney scarring by blocking TGF‐β signals [126]. PGC‐1α counteracts its low expression in diabetic muscles by promoting mitochondrial biogenesis [127], activating thermogenesis in brown fat to reduce blood sugar and fat levels, and cooperating with PPARα to improve muscle glucose use while suppressing hepatic gluconeogenesis [128]. The pathway enables a multifaceted diabetes intervention by simultaneously improving insulin signaling (AMPK‐dependent), normalizing metabolic flux (SIRT1‐mediated), and restoring mitochondrial function (PGC‐1α‐driven). These discoveries highlight the AMPK/SIRT1/PGC‐1α system as a key controller of diabetes development, presenting new treatment possibilities that target insulin function, sugar processing, and fat regulation through precise pathway adjustments.

Obesity, primarily caused by chronic energy intake exceeding expenditure, leads to excessive fat accumulation [129]. The core pathogenesis involves disrupted energy homeostasis. When energy intake surpasses adipose tissue storage capacity, circulating lipids accumulate in non‐adipose tissues, inducing lipotoxicity and pathophysiological alterations [130]. AMPK serves as a crucial cellular energy sensor that activates during energy deprivation to restore metabolic balance through complex signaling pathways [131]. Notably, both obese patients and animal models exhibit reduced AMPK activity [132, 133]. High‐fat diet‐induced obesity suppresses AMPK phosphorylation and subsequent autophagy, correlating with depressive and anxiety‐like behaviors in mice [134, 135]. Concurrently, obesity suppresses SIRT1 expression and activity, impairing its deacetylation of downstream targets [136] (Table 1). Research demonstrates that SIRT1 overexpression upregulates PPARγ mRNA levels, enhances Akt protein expression/activity, while downregulating hepatic FAS and ChREBP expression, collectively improving insulin sensitivity and reducing hepatic lipogenesis [137, 138]. Furthermore, SIRT1‐mediated PGC‐1α deacetylation enhances its transcriptional activity, promoting mitochondrial biogenesis and fatty acid oxidation to increase energy expenditure and thermogenesis [139]. Thus, the dysregulation of AMPK and SIRT1 signaling in obesity not only disrupts metabolic homeostasis but also contributes to associated neurobehavioral and hepatic complications, highlighting their potential as therapeutic targets for metabolic and psychiatric disorders.

Comprehensive mechanistic studies using adipocyte and hepatocyte models reveal that AMPK activation potently inhibits lipogenesis while promoting fatty acid oxidation. Specifically, activated AMPK phosphorylates and inhibits ACC, reducing malonyl‐CoA production and fatty acid synthesis, while upregulating OCTN2 to facilitate mitochondrial fatty acid transport and oxidation [140]. AMPK further amplifies these effects by modulating SIRT1/PGC‐1α activity, enhancing mitochondrial function and energy metabolism [141]. In obese murine models, AMPK/SIRT1 pathway activation reduces adiposity, enhances thermogenesis, and suppresses inflammation, ameliorating diet‐induced metabolic dysfunction [142]. These findings underscore the central role of AMPK/SIRT1 signaling in coordinating lipid metabolism and mitochondrial function, offering a promising therapeutic avenue for obesity‐related metabolic disorders through targeted pathway activation.

Coronary artery disease (CAD) is the top cause of heart‐related deaths. It happens when heart arteries narrow or get blocked by plaque buildup (Table 1). This reduces blood flow to the heart muscle. It can lead to serious problems like chest pain and heart attacks [143]. Scientists now believe the AMPK/SIRT1/PGC‐1α pathway could help treat CAD. AMPK activation protects the heart in two main ways. First, it helps keep artery lining cells alive [144]. Second, it changes how ACC works, which affects artery hardening [145]. Recent studies further elucidate AMPK's multifaceted role in CAD. In a large animal model of chronic myocardial ischemia, the GLP‐1 agonist Semaglutide was shown to improve myocardial perfusion and performance, an effect associated with increased activation of the endothelial‐protective AMPK pathway and downstream eNOS [146]. Additionally, AMPK activation also directly inhibits cardiomyocyte pyroptosis, a pro‐inflammatory cell death process implicated in coronary microembolization (CME)‐induced injury, via the AMPK/SIRT1/NLRP3 signaling axis [147]. Both AMPK and SIRT1 levels drop in CAD patients. Raising these levels with medicine might help [148]. Notably, the AMPK/SIRT1 axis also plays a crucial role in modulating atherosclerotic plaque stability. In diabetic settings, activation of AMPK and SIRT1 has been shown to enhance macrophage autophagy and reduce plaque vulnerability via pathways involving RAGE/LKB1/AMPK1/SIRT1, thereby stabilizing advanced atherosclerotic lesions [149]. A recent study found that Semen Ziziphi Spinosae extract reduces heart cell death by activating this pathway [150]. This research suggests new ways to treat CAD. The focus would be on protecting blood vessels, controlling metabolism, and preventing cell death. More studies are needed to find the best treatments. Scientists also need to understand exactly how this pathway works. They must check long‐term results in patients. This approach could lead to better, more targeted care for CAD.

Myocardial ischemia–reperfusion injury (MIRI) occurs when blood flow returns after a heart blockage but causes additional damage. This leads to cell death, irregular heartbeats, and weakened heart function [151]. The injury occurs through two sequential phases. Initially, oxygen deprivation depletes cellular ATP stores and disrupts ionic homeostasis. Subsequently, reperfusion generates excessive ROS that oxidatively damage lipids, proteins, and nucleic acids [152, 153] (Table 1). The AMPK/SIRT1/PGC‐1α pathway helps protect against MIRI in multiple ways. First, it reprograms cellular metabolism and combats oxidative stress through AMPK activation, which inhibits detrimental autophagy while preserving essential mitochondrial quality control [154]. Studies show AMPK acts as an energy sensor, reducing cell death and energy waste [155]. Second, it shields mitochondria by boosting antioxidant activity, lowering toxic ROS, and improving energy production [156, 157, 158, 159]. Key benefits include reducing oxidative stress, restoring energy balance, protecting mitochondria, and preventing cell death. Together, these effects help heart cells survive and recover. Better understanding this pathway could lead to new treatments for MIRI.

The brain needs constant oxygen and glucose to function properly. Hypoxic–ischemic brain injury (HIE) occurs when blood flow and oxygen to the brain suddenly stop during birth. This injury causes multiple problems including energy failure, oxidative stress, blood–brain barrier damage, brain inflammation, nerve cell toxicity, and blood vessel injury (Table 1) [160, 161, 162]. While cooling therapy helps, its benefits are limited [163], so we need better treatments. Mitochondria play a key role in HIE because they produce energy for brain cells. Helping mitochondria grow and function better could be an effective treatment [164]. When oxygen levels drop, AMPK activates and turns on SIRT1/PGC‐1α signaling. PGC‐1α works with NRF1 to increase UCP2 and TFAM, which helps mitochondria stay healthy, protects brain cells from stress, lowers harmful ROS, and keeps metabolism stable [165]. Studies show AMPK activation helps by reducing scar tissue formation, improving mitochondrial cleanup, and preventing brain cell death [166, 167, 168]. SIRT1 activation also fights inflammation by affecting the Nrf2–NF‐κB pathway, which decreases harmful chemicals and saves brain cells [169, 170]. Since SIRT1 helps control PGC‐1α [171], boosting the SIRT1–PGC‐1α–TFAM pathway improves mitochondria, reduces oxidative stress, and prevents cell death in HIE [172]. The AMPK/SIRT1/PGC‐1α pathway controls multiple aspects of HIE damage. It helps maintain energy, strengthens mitochondria, reduces inflammation, and protects brain cells. Targeting this pathway could lead to better treatments that improve outcomes for babies with HIE.

Ischemic stroke is the most common type of stroke, causing brain damage when blood flow stops. Restoring blood flow is the main treatment, but paradoxically can also cause additional harm to brain cells—this is called cerebral ischemia–reperfusion injury (CIRI) [173, 174]. The AMPK/SIRT1/PGC‐1α pathway helps protect the brain during CIRI by maintaining energy balance, reducing oxidative damage, and preventing cell death (Table 1). Following CIRI, AMPK exerts neuroprotection through two primary mechanisms. It modulates inflammatory responses by altering immune cell activity and inducing cytoprotective autophagy [175, 176]. Additionally, AMPK maintains mitochondrial homeostasis by facilitating damaged organelle clearance and regulating fission processes, with AMPK inhibition exacerbating cell death by impairing these quality control mechanisms [177, 178, 179]. SIRT1 and PGC‐1α function cooperatively in downstream pathways. SIRT1 activates SIRT3 to mitigate cerebral injury, apoptosis, oxidative damage, and mitochondrial dysfunction [49, 180]. Meanwhile, PGC‐1α enhances mitochondrial capacity by regulating biogenesis and function through the NRF1/TFAM axis [181]. Together, this pathway helps reprogram cell metabolism, repair oxidative damage, and optimize mitochondria. Future research should study how this pathway changes over time, how it interacts with brain blood vessels, and how to develop comprehensive protection strategies. These studies may lead to more precise stroke treatments.

Chronic kidney disease (CKD) is characterized by progressive renal fibrosis, oxidative stress, and sustained inflammation [117, 182, 183, 184], with disease progression primarily driven by dysfunction of the AMPK/SIRT1/PGC‐1α signaling axis [185]. The malfunctioning AMPK/SIRT1/PGC‐1α pathway worsens chronic kidney disease through three connected problems (Table 1). First, when SIRT1 levels drop, it overactivates the NLRP3 inflammasome, causing excessive IL‐1β/IL‐18 release that damages kidney tubes [186]. Studies confirm CKD patients with lower SIRT1 have higher inflammation markers [187]. Second, when AMPK doesn't work properly, it boosts TGF‐β/Smad3 signals that activate scar‐forming cells and deposit harmful proteins [188, 189]. Research shows mice lacking AMPKα2 develop worse scarring [186, 187], while inactive SIRT1 prevents Smad3 breakdown, making scarring worse [190]. Third, low PGC‐1α impairs mitochondria's ability to produce energy in kidney cells, with CKD patients showing lower energy levels and more oxidative stress [191, 192]. Therapeutic modulation of this pathway yields multifaceted protection. SIRT1 exerts anti‐inflammatory effects via NLRP3 inflammasome suppression, with AMPK/SIRT1 cooperation inhibiting fibrotic progression through TGF‐β pathway regulation. Concurrently, PGC‐1α mediates mitochondrial rehabilitation to reestablish metabolic equilibrium. Translational evidence demonstrates metformin‐induced AMPK activation decreases inflammatory mediators [193], puerarin‐mediated SIRT1 elevation preserves renal function [194], and PGC‐1α overexpression confers hypoxia resistance in renal epithelial cells [195]. In summary, the AMPK/SIRT1/PGC‐1α pathway serves as a central hub integrating multiple pathological processes in CKD (inflammation, fibrosis, and metabolic dysregulation), making it a highly promising therapeutic target. By orchestrating a cross‐scale regulatory network connecting inflammation, fibrosis, and energy metabolism, targeted activation of this pathway may restore renal microenvironmental homeostasis, offering a novel approach for developing precision intervention strategies in CKD.

Chronic obstructive pulmonary disease (COPD) involves ongoing airway inflammation, an imbalance between protein‐digesting enzymes and their inhibitors, and oxidative damage. These problems worsen due to a malfunctioning AMPK/SIRT1/PGC‐1α pathway [196, 197]. This faulty signaling speeds up COPD through three connected problems. First, cigarette smoke causes oxidative damage while lowering SIRT1 levels in both COPD patients and lab animals. When SIRT1 can't properly modify FOXO3, it reduces protective antioxidant enzymes [198, 199, 200]. Damaged DNA markers in COPD lungs directly link to poor SIRT1 function [173], proving its importance. Second, weak AMPK activity in lung immune cells allows harmful inflammation signals to spread, increasing damaging chemicals like TNF‐α/IL‐8 [201]. Mice lacking AMPKα1 develop worse lung inflammation and emphysema when exposed to smoke [202]. Third, low SIRT1 levels overactivate an enzyme called p300, which disrupts the balance between tissue‐destroying MMP‐9 and its inhibitor α1‐antitrypsin, leading to lung damage [203, 204]. However, treatments targeting this pathway can help. The SIRT1‐FOXO3 connection boosts antioxidants, AMPK blocks inflammation signals, and SIRT1 rebalances destructive enzymes. Emerging evidence highlights multiple pharmacologic agents with distinct mechanisms. Resveratrol potentiates SIRT1‐mediated activation of endogenous antioxidant systems [205], whereas quercetin restores AMPK‐dependent cytoprotective pathways in alveolar epithelium [206]. Nicotinamide mononucleotide promotes macrophage phenotypic switching to tissue‐reparative states [207]. Beyond these effects, SIRT1 enzymatically rebalances the MMP‐9/TIMP‐1 axis via targeted protein modifications [203, 204]. These findings highlight how the AMPK/SIRT1/PGC‐1α pathway controls COPD's key problems and could lead to better treatments. In conclusion, dysfunction of the AMPK/SIRT1/PGC‐1α pathway represents a pivotal mechanism in COPD pathogenesis (Table 1). Novel therapeutic opportunities emerge from targeted activation strategies that simultaneously engage antioxidant defenses, anti‐inflammatory pathways and proteostasis restoration mechanisms. Elucidating the pathway's dynamic regulatory network within the pulmonary immunometabolic microenvironment, coupled with developing tissue‐specific delivery systems to enhance targeting efficacy, will facilitate a paradigm shift from symptomatic management to disease modification in COPD treatment.

Researchers have made significant advances in developing AMPK activators, with metformin and AICAR standing out as key examples showing protective effects across multiple organs (Figure 3). Metformin works by blocking mitochondrial complex I, which activates AMPK through phosphorylation. Metformin's mechanism provides multiple therapeutic advantages. It enhances metabolic function by promoting glucose uptake in liver, muscle and adipose tissue while suppressing hepatic gluconeogenesis, establishing its position as a first‐line diabetes therapy [208]. Additionally, it confers cardiorenal protection through AMPK‐mediated reduction of inflammatory responses, restoration of autophagic flux and inhibition of apoptosis [209]. In diabetic kidney disease specifically, metformin activates the AMPK/SIRT1 axis to mitigate oxidative damage and prevent excessive autophagy [210]. Metformin demonstrates extended therapeutic potential in oncology and musculoskeletal health. It induces cancer cell apoptosis via AMPK/SIRT1‐dependent degradation of NF‐κB p65 [211], while protecting against osteoarthritis by enhancing chondrocyte autophagy, inhibiting apoptosis and regulating cholesterol metabolism [212]. Regarding hepatic and vascular systems, metformin selectively inhibits PGC‐1α‐mediated hepatic gluconeogenesis [213] and enhances telomerase activity through AMPK/PGC‐1α phosphorylation to prevent arterial stiffening [214]. The AMP‐mimetic AICAR operates through unique pharmacologic mechanisms as a direct AMPK agonist. Its metabolic reprogramming capabilities include potentiation of fatty acid β‐oxidation, GLUT4‐mediated glucose uptake and glycolytic flux [215]. AICAR's organoprotective properties manifest differentially across tissues: it reduces renal oxidative stress and inflammation while maintaining SIRT1 homeostasis during ischemic injury [216]; reverses neurobehavioral abnormalities and AMPK/SIRT1 deficits in chronic stress models [217]; and ameliorates obesity‐induced insulin resistance through SIRT1‐dependent pathways [218]. Muscle‐specific responses reveal time‐dependent PGC‐1α regulation, where transient AICAR exposure upregulates PGC‐1α and glycogen synthesis, but prolonged treatment elicits opposite effects [213]. These activators provide novel therapeutic strategies for metabolic disorders, organ damage and degenerative diseases through precise modulation of AMPK networks. Future research should focus on developing tissue‐selective activators and elucidating spatiotemporal dynamics in microenvironmental contexts, aiming to overcome off‐target limitations and achieve precise metabolic reprogramming.

SIRT1 activators show great promise for treating age‐related diseases, with SRT1720 and nicotinamide mononucleotide (NMN) standing out as particularly effective options that work in different ways (Figure 3). SRT1720 selectively activates SIRT1 to provide cellular protection through two primary mechanisms. First, it enhances PGC‐1α transcriptional activity to mitigate toxin‐induced cellular damage, as demonstrated in paraquat exposure models [219]. Second, it ameliorates vascular dysfunction in atherosclerosis by restoring mitochondrial homeostasis and suppressing proinflammatory signaling pathways [220]. Meanwhile, NMN works differently as it helps produce NAD⁺, which then activates SIRT1's protein‐modifying abilities. This gives NMN its brain‐protecting effects, seen in its ability to reduce inflammation and oxidative stress in the memory centers of mice with severe infections [221]. NMN also helps maintain healthy metabolism in diabetes by preventing the usual drop in SIRT1 and PGC‐1α activity, using its protein‐modifying power to shield against high blood sugar damage [222]. These two compounds collectively illustrate how SIRT1 activation, whether achieved directly through SRT1720 or indirectly via NMN‐mediated NAD⁺ elevation, can offer substantial therapeutic benefits for multiple age‐related conditions. Considering both the limited availability of SIRT1‐targeting drugs and its crucial role in lifespan regulation, researchers must prioritize two critical areas. First, they should explore the therapeutic potential of SIRT1 activators for neurodegenerative diseases such as AD and age‐related metabolic disorders including T2DM. Second, they need to clarify how tissue‐specific deacetylation networks interact with epigenetic regulation. The development of blood–brain barrier‐permeable SIRT1 allosteric activators, combined with deciphering their tissue‐specific epigenetic remodeling mechanisms, may overcome current therapeutic bottlenecks in age‐related diseases. This approach could ultimately catalyze a paradigm shift from lifespan extension to healthspan prolongation.

The PGC‐1α agonist ZLN005 shows protective effects across multiple organs through three key mechanisms, making it a promising new treatment for metabolic and degenerative diseases (Figure 3). For heart protection, ZLN005 reduces oxidative damage caused by chemotherapy drugs, improves cellular antioxidant defenses, prevents harmful tissue changes, and slows the progression of heart muscle disease [223]. In the nervous system, it activates mitochondrial protein production, maintains proper energy levels in neurons, and helps brain cells survive under stressful conditions [224]. The compound also protects against damage caused by restored blood flow after oxygen deprivation in organs like the heart, brain and kidneys by boosting mitochondrial growth and reducing harmful reactive oxygen species [225]. By directly targeting the central mitochondrial energy production system, ZLN005 offers an innovative treatment approach that addresses the root causes of these disorders rather than just their symptoms. This compound offers innovative therapeutic strategies for metabolic and degenerative diseases by directly modulating core mitochondrial energy metabolism pathways. Future research should focus on developing tissue‐specific allosteric activators coupled with spatiotemporally precise drug delivery systems to decipher dynamic metabolic reprogramming effects. Addressing current organ‐specific delivery challenges could enable a fundamental transformation in treatment approaches, moving beyond symptomatic management to achieve genuine tissue regeneration.

Caloric restriction (CR), which means eating fewer calories while still getting essential nutrients, is a proven way to improve health and extend lifespan without genetic changes (Figure 3) [242]. It works by carefully adjusting cell cleanup processes, nutrient signals, and key energy pathways. CR helps maintain metabolic balance by reducing cellular stress, lowering blood sugar, and improving insulin response [243]. It activates energy‐sensing pathways by increasing the NAD⁺/NADH ratio to boost SIRT1 activity, while also enhancing AMPK activation and promoting PGC‐1α‐driven mitochondrial growth [244, 245]. For heart health, CR improves energy use in heart cells through the AMPK/SIRT1/PGC‐1α system and makes the heart more resistant to stress [246]. These combined effects boost mitochondrial production, improve metabolic balance, and reduce cellular stress, effectively slowing aging while improving metabolic health and heart function. Important next steps include using advanced testing methods to determine personal calorie restriction responses, creating detailed biomarker profiles based on AMPK/SIRT1/PGC‐1α pathway activity, developing timed eating plans that copy calorie restriction benefits, and applying AI technology to create personalized anti‐aging treatments. This approach will move us from general diet changes to customized health plans targeting specific biological mechanisms, transforming how we prevent age‐related diseases. Research should especially examine how different tissues and genetic backgrounds respond to identify the most effective treatments with the fewest side effects, helping create tailored solutions for aging populations.

Exercise triggers metabolic changes by activating the AMPK/SIRT1/PGC‐1α pathway through three key steps (Figure 3). First, during the energy stress phase, muscles quickly take up glucose while breaking down glycogen and making new glucose, leading to ATP depletion and an increased AMP/ATP ratio that activates AMPK [247, 248]. Second, this AMPK activation boosts PGC‐1α production, remodeling mitochondria to burn more fat [249]. Third, exercise protects the brain by improving cell cleanup through AMPK‐SIRT1 signaling [250] and reducing brain inflammation in aging animals [251]. Interestingly, the plant compound DMC enhances these exercise benefits by strengthening AMPK/SIRT1/PGC‐1α signaling in muscles and fat, improving metabolism, reducing inflammation and maintaining energy balance [252]. Collectively, these findings highlight the AMPK/SIRT1/PGC‐1α pathway as a central orchestrator of exercise‐induced metabolic adaptation, bridging acute energy stress with long‐term tissue remodeling, while pharmacological mimetics like DMC may synergize with physical activity to optimize metabolic health.