SIRT1-Mediated Redox and Senescence Regulation in Cancer: Mechanisms and Therapeutic Implications

Protein acetylation is a key post-translational modification that regulates numerous aspects of protein function and gene expression [14]. This process involves the covalent transfer of an acetyl group from acetyl-CoA to specific sites on proteins, most commonly to either the α-amino group at the N-terminus or the ε-amino group of lysine residues [15].

Acetylation at the N-terminal α-amino group, referred to as Nα-acetylation, generally occurs co-translationally during protein synthesis [16]. This modification is irreversible and primarily affects protein stability and degradation, thereby influencing the overall half-life of proteins within the cell. Nε-acetylation, which targets internal lysine residues, is a reversible process that dynamically modulates protein behavior. This type of acetylation plays a critical role in controlling protein–protein interactions, subcellular localization, DNA-binding activity, and the transcriptional potential of various factors. These acetylation reactions are catalyzed by lysine acetyltransferases, a diverse group of enzymes that act on both histone and non-histone substrates [17]. Some of the well-known KATs include enzymes that target histones H3 and H4 to promote chromatin relaxation and transcriptional activation, while others acetylate key transcription factors, such as p53, FOXO1, and NF-κB, thereby influencing cellular responses to oxidative stress and DNA damage [18]. In addition to gene regulation, certain acetyltransferases contribute to genome stability and DNA repair by acetylating the components of the DNA damage response machinery. Through these multifaceted functions, acetylation provides cells with a versatile mechanism to finely tune physiological processes, adapt to environmental stresses, and promote survival and proliferation in pathological contexts, such as cancer [4].

Cancer cells survive oxidative stress, DNA damage, metabolic imbalances, and immune challenges by precisely regulating adaptive pathways via protein acetylation [19]. In addition to its classical role in epigenetic regulation, acetylation dynamically alters the activity, stability, localization, and interactions of transcription factors and signaling proteins. This multifaceted control enables cancer cells to reprogram their fate and survive under hostile conditions. Acetylation enables diverse adaptive mechanisms in cancer cells [19]. These functions can be broadly categorized as transcriptional regulation, protein stability, and subcellular localization (Figure 1).

Acetylation is an inherently reversible process; therefore, deacetylation serves not only as a counteracting mechanism but also as a crucial axis for transcriptional repression and the regulation of protein function [23]. Deacetylases can be broadly divided into two major classes. The first comprises Zn²⁺-dependent histone deacetylases (HDACs), which promote transcriptional repression by compacting chromatin structure. The second category includes NAD-dependent sirtuins, which couple their activity to the cellular metabolic state and finely tune gene expression, stress responses, and signaling pathways [24]. Thus, although both HDACs and sirtuins mediate deacetylation, they exhibit distinct modes of action and operate in different biological contexts.

SIRT1 is a NAD⁺-dependent deacetylase that plays a central role in cellular metabolism, aging, and survival. NAD⁺ serves as both a cofactor and direct substrate for SIRT1 activity [30]. During the deacetylation of lysine residues on target proteins, NAD⁺ is cleaved into nicotinamide, O-acetyl-ADP-ribose, and acetate [31]. NAD⁺ is regenerated in cells in limited amounts; therefore, its availability is a key determinant of SIRT1 enzymatic activity. In cancer cells, the NAD⁺–SIRT1 signaling pathway contributes to tumor survival by regulating redox homeostasis and suppressing cellular senescence [32]. When NAD⁺ levels are maintained or elevated, SIRT1 activity is enhanced, which inhibits senescence-related pathways and promotes cancer cell proliferation and survival [33]. This regulatory axis can be further strengthened by supplementation with NAD⁺ precursors, such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), which elevate intracellular NAD⁺ levels and consequently augment SIRT1 activity, reinforcing redox balance and resistance to senescence in cancer cells [34].

Beyond salvage and precursor supplementation pathways, nicotinamide N-methyltransferase (NNMT) is a master regulator of the NAD⁺-SAM-SIRT1 metabolic axis [36]. NNMT catalyzes the methylation of nicotinamide to 1-methylnicotinamide (1-MNA) using S-adenosylmethionine (SAM) as the methyl donor [37]. Through this reaction, NNMT simultaneously depletes NAD⁺ precursors and consumes SAM, thereby reducing intracellular NAD⁺ availability, altering the methylation potential, and indirectly modulating NAD⁺-dependent enzymes, including SIRT1 [38]. Ulanovskaya et al. demonstrated that NNMT rewires the cellular methylation capacity by draining SAM pools, thus coupling NAD⁺ salvage metabolism with epigenetic regulation [38]. Elevated NNMT expression has been consistently reported in multiple cancers, where it enhances tumorigenicity, drives epigenetic reprogramming, promotes redox imbalance, and contributes to drug resistance [39]. NNMT should thus be regarded not as a solitary oncogenic effector but as a pivotal metabolic checkpoint that indirectly regulates SIRT1 activity, positioning it at the intersection of NAD⁺ and SAM metabolism in cancer [40].

In addition to enzymatic regulators, such as NNMT, intracellular NAD⁺ concentrations fluctuate dynamically in response to metabolic stress, including energy deficiency, oxidative stress, and nutrient scarcity [41]. Under such conditions, NAD⁺ levels may transiently increase, leading to enhanced SIRT1 activation. Cancer cells exploit this adaptive mechanism by upregulating the NAD⁺–SIRT1 axis to reinforce antioxidant defenses, resist oxidative damage, and evade senescence [35]. Given its central role in regulating both NAD⁺ and SAM metabolism, therapeutic targeting of NNMT has gained attention as a strategy to restore redox balance and epigenetic integrity in tumors [42,43]. Several small-molecule NNMT inhibitors have been developed and are currently under preclinical investigation, demonstrating promising efficacy in overcoming chemoresistance and suppressing tumor progression [44,45]. (Figure 2)

SIRT1 exerts its deacetylase activity in a manner that is highly sensitive to the cellular redox environment [46]. SIRT1 function is dependent on the availability of NAD⁺; therefore, its activity dynamically responds to metabolic and oxidative stress conditions [47]. This suggests that SIRT1 is a redox-sensitive regulator that integrates environmental signals into adaptive cellular responses. SIRT1 promotes cancer cell survival and adaptation under stressful conditions by deacetylating various transcription factors and metabolic regulators. Representative targets include p53, FOXO family transcription factors, PGC-1α, and NF-κB [46]. By modulating the activity of these factors in a redox-dependent manner, SIRT1 enables cancer cells to sustain growth and resist metabolic and oxidative stress.

SIRT1 deacetylates a range of transcription factors involved in antioxidant defense, mitochondrial regulation, and inflammatory signaling to maintain redox homeostasis under oxidative stress. The best-characterized redox-sensitive substrates include p53, members of the FOXO family (FOXO1/3/4), PGC-1α, and NF-κB, all of which orchestrate essential cellular responses to redox imbalances. p53 is a central mediator of apoptosis under oxidative stress and is activated by ROS accumulation. Acetylation at K382 enhances proapoptotic transcriptional activity, whereas SIRT1-mediated deacetylation suppresses this function, thereby protecting cancer cells from ROS-induced apoptosis [11]. FOXO transcription factors regulate the expression of antioxidant enzymes, such as SOD2 and catalase. Deacetylation by SIRT1 augments transcriptional activity, enhances antioxidant capacity, and promotes resistance to oxidative damage [12]. PGC-1α acts as a master regulator of mitochondrial biogenesis and oxidative metabolism, and stimulates detoxifying enzymes, such as glutathione peroxidase 1 (GPx1). Deacetylation by SIRT1 enhances mitochondrial efficiency and supports redox balance, particularly under metabolic stress [32]. NF-κB, a pivotal transcription factor in inflammation and SASP, is strongly activated by oxidative stimuli. SIRT1 deacetylates the p65 subunit, thereby reducing pro-inflammatory gene expression and restraining chronic inflammation within the tumor microenvironment [33]. Moreover, elevated NAD⁺ levels under stress conditions further amplify SIRT1 activity and substrate deacetylation, collectively enabling cancer cells to adapt to oxidative, inflammatory, and metabolic stress (Figure 3).

The tumor suppressor, p53, is a redox-sensitive transcription factor that initiates cell cycle arrest, apoptosis, and senescence in response to genotoxic stress, oxidative damage, and oncogene activation [50]. One of the key regulatory post-translational modifications of p53 is acetylation at K382 by CBP/p300, which enhances its DNA-binding capacity and transcriptional activation of downstream effectors, such as p21^CIP1, PUMA, and BAX [21,51]. These target genes reinforce senescence and apoptotic responses [52]. SIRT1 is frequently overexpressed in cancer cells and functions as a redox-regulated deacetylase that removes the acetyl group from p53 at K382, thereby repressing its transcriptional activity. This results in the attenuated expression of p21 and pro-apoptotic genes, enabling cancer cells to evade senescence even under persistent DNA damage or oxidative stress [53]. This mechanism is particularly critical in the early stages of tumorigenesis, where oncogene-induced senescence typically acts as a fail-safe mechanism [54]. However, SIRT1-mediated p53 inactivation blocks this barrier, thereby facilitating malignant progression [55]. For instance, in medulloblastoma models, p53 deacetylation is correlated with p21 suppression and escape from senescence [56]. Similarly, in melanoma, defective p53 acetylation impairs p21 induction despite upstream checkpoint activation via CHEK2 [51]. In addition to its canonical role in cell-cycle arrest, acetylated p53 contributes to the regulation of cellular senescence and tumor suppression by influencing inflammatory signaling, immune surveillance, and metabolic homeostasis. Thus, SIRT1-mediated deacetylation of p53 impairs direct growth arrest, suppresses antitumor immunity, and accelerates malignant transformation [57,58].

FOXO1 is a redox-responsive transcription factor that promotes cellular senescence under oxidative stress or DNA damage by upregulating antioxidants, such as manganese superoxide dismutase (MnSOD) and catalase, as well as cell cycle inhibitors, such as p27^Kip1 and GADD45 [31,59]. In response to oncogenic or metabolic stress, FOXO1 contributes to the establishment of a senescent phenotype via its transcriptional activity. However, in cancer cells, SIRT1 reprograms FOXO1 via site-specific deacetylation of lysine residues (e.g., K242, K245, and K262) [60,61]. This post-translational modification induces a functional shift; FOXO1 downregulates pro-apoptotic targets, such as BIM and Fas, while sustaining or even enhancing antioxidant gene expression [31,62]. Consequently, cancer cells can efficiently neutralize intracellular ROS without triggering senescence pathways. Moreover, FOXO1 may indirectly modulate transcriptional regulators, such as AP-1 and BACH2, which are involved in redox adaptation, differentiation, and senescence control [63]. Oncogenic rewiring of the SIRT1–FOXO1 axis has been reported in multiple cancer types, including non-small cell lung cancer (NSCLC) and glioblastoma [64]. Collectively, SIRT1-mediated deacetylation of FOXO1 represents a crucial mechanism by which cancer cells evade senescence and apoptosis, while maintaining redox homeostasis.

FOXO3 is a redox-sensitive transcription factor activated by oxidative stress, energy deprivation, and DNA damage, and it typically promotes cell cycle arrest and senescence through the induction of p27^Kip1, GADD45, MnSOD, and catalase [65]. However, the SIRT1-mediated deacetylation of FOXO3 at multiple lysine residues (K242, K259, K271, K290, and K569) alters its transcriptional output and nuclear localization in cancer cells [66]. Deacetylated FOXO3 preferentially activates genes involved in antioxidant defense and autophagy, whereas the regulation of cell cycle inhibitors appears to be context-dependent and may vary across cell types and stress conditions [67]. In endometrial cancer, FOXO3 activates BNIP3, which initiates PINK1/Parkin-mediated mitophagy to remove damaged mitochondria and reduce ROS levels [67,68,69]. This process dampens oxidative damage signals and prevents senescence, thereby supporting cancer cell survival, proliferation, and therapeutic resistance. In gastric cancer, a positive feedback interaction between AMPK and FOXO3 has been suggested, which potentially amplifies FOXO3 activity and contributes to enhanced antioxidant defense and metabolic reprogramming [66,70]. Thus, SIRT1-FOXO3-mediated mitophagy and redox homeostasis are key mechanisms by which cancer cells evade senescence [68].

FOXO4 contributes to senescence by forming nuclear complexes with p53, stabilizing it in the nucleus and sustaining p21^CIP1 expression. This FOXO4–p53 interaction is critical for maintaining senescence-associated growth arrest [71,72]. While direct evidence for SIRT1-mediated deacetylation of FOXO4 is limited, K189 has been identified as a lysine residue sensitive to HDAC activity, suggesting possible modulation by Class III HDACs, such as SIRT1 [38]. Disruption of the FOXO4-p53 complex causes p53 translocation to the mitochondria, where it activates caspase-dependent apoptosis. This mechanism is particularly relevant in therapy-induced senescence (TIS), which is triggered by doxorubicin or cisplatin. In cancer cells with elevated SIRT1 activity, destabilization of the FOXO4-p53 complex may facilitate escape from the TIS and promote re-entry into the cell cycle. Recent therapeutic strategies, including FOXO4-DRI peptides and CPP-CAND, aim to selectively disrupt FOXO4-p53 interactions to induce senolysis [72]. Collectively, these results suggest that SIRT1 acts as a molecular switch that determines whether FOXO4-mediated senescence is sustained or bypassed in cancer cells.

PGC-1α is a transcriptional coactivator that orchestrates mitochondrial biogenesis, oxidative phosphorylation, and antioxidant defense, playing a central role in redox adaptation in cancer cells [38]. Under metabolic stress and excessive ROS, PGC-1α activates genes, such as NRF1/2, TFAM, COX IV, SOD2, GPx1, and PRDX3, thereby sustaining ATP production and detoxifying ROS [39]. PGC-1α activity is enhanced by SIRT1-dependent deacetylation, with lysine 778 (K778) proposed as a potential regulatory site [40]. Enhanced NAD⁺ availability boosts SIRT1 activity, leading to activation of PGC-1α and its downstream partners, including FOXO1, NRF1/2, and ERRα [41]. This transcriptional program suppresses ROS accumulation and DNA damage signaling, thereby attenuating senescence induction via p53- or FOXO-mediated pathways [38,42]. Additionally, PGC-1α has been implicated in modulating the NAD⁺/NADH balance, engaging with the AMPK–SIRT1-FOXO1 axis, and integrating mitochondrial stress responses, supporting cancer cell metabolic flexibility and resistance to therapeutic stress [42]. Thus, the SIRT1–PGC-1α axis constitutes a critical senescence-evasion mechanism by preserving mitochondrial integrity and redox balance in cancer cells, particularly under TIS conditions.

NF-κB is a redox-sensitive transcription factor that plays a central role in regulating inflammation, cell survival, and the SASP [73]. Under oxidative stress, NF-κB is activated through the canonical IKK–IκBα signaling cascade, wherein IκBα is phosphorylated and degraded, allowing the p65 (RelA) subunit to translocate into the nucleus [74]. Once in the nucleus, p65 undergoes post-translational modifications that modulate its transcriptional activity [75]. Among these, acetylation at lysine 310 (K310) is particularly critical. It enhances the transcriptional potency of NF-κB without altering DNA-binding affinity, thereby promoting the expression of pro-inflammatory and pro-senescent genes, including IL-6, IL-8, and TNF-α hallmark components of the SASP [76,77]. Persistent oxidative stress in senescent cells leads to sustained K310 acetylation, resulting in chronic NF-κB activation and continuous SASP secretion [78]. This establishes a pro-inflammatory microenvironment that reinforces senescence, induces paracrine senescence in neighboring cells, and paradoxically supports tumor progression and immune evasion.

SIRT1, a NAD⁺-dependent deacetylase activated under oxidative and metabolic stress, counteracts this process by deacetylating p65 at K310 in a redox-sensitive manner. Through this deacetylation, SIRT1 suppresses the transcriptional activity of NF-κB, even in the presence of upstream activating signals, thereby attenuating SASP factor expression and limiting senescence-associated inflammation. Under tumorigenic conditions, the SIRT1-mediated suppression of NF-κB activity confers a selective advantage by enabling senescent evasion and reducing immune surveillance. This contributes to the maintenance of a redox-adapted tumor-permissive microenvironment. Therapeutically, the inhibition of SIRT1 to restore p65 K310 acetylation and reactivate the SASP may represent a promising strategy to trigger tumor-suppressive senescence and enhance the immune-mediated clearance of cancer cells [79].

Recent studies have revealed that SIRT1 not only governs the intracellular redox balance but also plays a key role in shaping the tumor immune microenvironment. Through the deacetylation of transcription factors like FOXO1 and NF-κB, SIRT1 suppresses the expression of pro-inflammatory cytokines and antigen-presenting machinery, thereby promoting immune evasion in cancer. Furthermore, single-cell transcriptomic and redox profiling technologies have revealed significant heterogeneity in SIRT1 expression and redox adaptation among tumor-infiltrating immune cells, especially T-cells and myeloid populations [80]. Notably, redox-resistant immune subpopulations exhibit elevated SIRT1 activity, reinforcing immunosuppression and therapeutic resistance. These insights suggest that targeting the SIRT1–redox axis in defined immune cell subsets may provide promising avenues for combinatorial strategies involving immune checkpoint blockade [81].

In ovarian cancer, SIRT1 facilitates the cellular adaptation to oxidative stress by modulating key redox-sensitive transcription factors. Deacetylation of p53 at K382 suppresses the transcription of pro-apoptotic and pro-senescent genes, such as p21, PUMA, and BAX, thereby inhibiting cell cycle arrest and apoptosis [82,83]. Deacetylation of FOXO1 and FOXO3 at residues K242, K245, K259, K262, and K291 enhances the expression of antioxidant genes, including MnSOD, catalase, and GADD45, thereby contributing to ROS detoxification [23]. PGC-1α deacetylation promotes mitochondrial biogenesis and oxidative phosphorylation, maintaining energy production and limiting ROS generation [84]. Additionally, SIRT1 upregulates autophagy-related genes, such as LC3 and Beclin-1, promoting autophagy and enhancing resistance to chemotherapeutic stress [85]. According to Peck et al., inhibition of SIRT1 increases p53 acetylation and triggers apoptosis, whereas elevated SIRT1 activity correlates with earlier relapse and reduced sensitivity to ROS-inducing agents in patients with ovarian cancer [86]. Ovarian cancer comprises multiple histological subtypes with distinct origins, molecular features, and clinical characteristics. For example, endometrioid carcinoma is often associated with endometriosis and displays lower-grade malignancy, whereas high-grade serous carcinoma (HGSC) typically originates from the fallopian tube epithelium and is characterized by aggressive growth, extensive genomic instability, and poor prognosis. The function of SIRT1 may differ across these subtypes owing to variations in redox microenvironments, p53 mutation status, and metabolic phenotypes. Future studies should investigate the subtype-specific roles of SIRT1 in redox adaptation and therapy resistance, particularly in HGSC, which is the most lethal form of ovarian cancer [87,88,89]. These findings collectively underscore the contribution of SIRT1 to understanding chemoresistance in ovarian cancer; however, they also highlight critical gaps. Most evidence is derived from cisplatin-resistant cell lines or xenograft models, which may not fully capture the heterogeneity of patient tumors. In addition, contradictory reports on SIRT1 expression across histological subtypes suggest that its role in therapy resistance is not uniform. Although SIRT1 inhibition remains a promising therapeutic strategy, its clinical translation requires validation in patient-derived models and stratification of cohorts according to histological subtype and redox profile

In breast cancer, SIRT1 promotes tumor progression by enhancing redox adaptation and suppressing senescence. Similar to ovarian cancer, SIRT1 deacetylates p53 at residue K382, which weakens stress-induced apoptotic responses and facilitates tumor survival. [90]. These finding underscores the role of SIRT1 in disabling canonical tumor-suppressive checkpoints, which is a major contribution to our understanding of redox adaptation in breast cancer. However, the evidence is largely based on in vitro models, and it remains uncertain whether similar suppression occurs across heterogeneous patient-derived tumors, particularly those with mutant p53 [88,91]. Deacetylation of FOXO3 at K242, K259, and K271 upregulates antioxidant enzymes, such as SOD2, catalase, and GPx1, thereby maintaining genomic stability under oxidative conditions [92]. In some breast cancer cells, SIRT1 deacetylates NF-κB (p65) at K310, thereby suppressing the transcription of pro-inflammatory and pro-senescent genes, such as IL-6 and IL-8. This contributes to the evasion of SASP-driven senescence and enhances resistance to redox-related therapies [93,94]. Parija et al. reported that SIRT1 inhibition in ERα-positive breast cancer enhances p53 activation and induces apoptosis. SIRT1 also deacetylates ERα, enhancing its transcriptional activity and promoting proliferation in hormone-responsive tumors [95]. Importantly, breast cancer is a heterogeneous disease comprising distinct molecular subtypes, including luminal A/B, HER2-enriched, and triple-negative breast cancer (TNBC), in addition to the classical ER-positive and ER-negative classifications. The function and prognostic implications of SIRT1 may substantially differ across these subtypes owing to their unique redox landscapes, hormone receptor status, and metabolic dependencies. Future studies should elucidate how SIRT1-mediated redox regulation contributes to therapeutic resistance, tumor progression, and immune evasion in each molecular subtype, particularly in aggressive forms, such as HER2-positive and TNBCs. Overall, SIRT1 overexpression in breast cancer is associated with increased malignancy, resistance to oxidative stress, and poor clinical outcomes, positioning SIRT1 as a key modulator of redox signaling and therapeutic escape [88,96]. Collectively, these findings indicate that SIRT1 is a key regulator of redox adaptation and senescence evasion in breast cancer. However, most evidence was from in vitro models or specific subtypes, prohibiting the generalizability to heterogeneous patient tumors. Moreover, conflicting reports suggest that SIRT1 function differs across molecular subtypes, from luminal to HER2+ and TNBC. Thus, while targeting SIRT1 remains promising, future studies must incorporate patient-derived models and stratify them according to the subtype and redox landscape to clarify whether SIRT1 inhibition can provide consistent clinical benefits.

In HCC, persistent oxidative stress resulting from chronic inflammation, viral infection, and hypoxia contributes to mitochondrial dysfunction and genomic instability [97]. Deacetylation of PGC-1α by SIRT1 enhances mitochondrial biogenesis, improves electron transport chain efficiency, and promotes fatty acid oxidation, thereby reducing mitochondrial ROS production [98]. SIRT1-mediated deacetylation of FOXO1/3 at K242, K259, and K271 induces the expression of antioxidant and DNA repair genes, such as MnSOD, catalase, and GADD45. Deacetylation of FOXO4 at K189 suppresses the transcription of proapoptotic and cell cycle inhibitory genes, thereby promoting cell survival [71,98,99]. SIRT1 modulation of p53 acetylation status, as observed in other cancers, contributes to apoptosis resistance in HCC. In addition, SIRT1 regulates autophagy to support tumor cell survival under metabolic stress [90]. According to Chan et al., pharmacological inhibition of SIRT1 induces apoptosis and reduces the proliferation of HCC cells [100]. Clinically, SIRT1 overexpression is associated with vascular invasion, metastasis, and sorafenib resistance, highlighting its potential as a prognostic biomarker and therapeutic target for aggressive liver cancers [101]. Collectively, these studies support the tumor-promoting role of SIRT1 in HCC through mitochondrial redox control and stress adaptation. However, most data are derived from HBV/HCV-related models, which limit their applicability to NASH- or alcohol-related HCC [100,102]. Furthermore, evidence of the stage-dependent dual role of SIRT1, tumor suppression in early lesions, and oncogenicity in advanced disease, remains underexplored. Therefore, patient cohort studies across different etiologies and disease stages are required to determine whether SIRT1 inhibition can be safely and effectively integrated into liver cancer therapy.

Patients with NSCLC are frequently exposed to chronic oxidative insults arising from environmental factors, such as cigarette smoke, air pollution, and persistent inflammation [103]. These redox stressors drive the sustained activation of NF-κB signaling and promote SASP, which contributes to tumor-promoting inflammation and paracrine senescence in neighboring cells [78]. SIRT1 counteracts this redox-driven proinflammatory state by deacetylating the p65 subunit of NF-κB at lysine 310 (K310), which is essential for full transcriptional activity [93]. Deacetylation at this residue reduces NF-κB's ability to induce SASP-related cytokines, including IL-6, IL-8, and TNF-α, thereby limiting chronic inflammation and suppressing senescence propagation [78,94]. In addition, in line with the findings in ovarian and breast cancers, SIRT1 suppresses p53 activity in lung cancer cells, aiding in redox adaptation and evasion [22]. Deacetylation of PGC-1α enhances mitochondrial biogenesis and oxidative phosphorylation, stabilizing redox homeostasis under metabolic stress [104]. SIRT1 also upregulates autophagy-related genes, such as LC3 and Beclin-1, promoting survival in hostile microenvironments. Collectively, these redox-adaptive responses foster immune evasion and therapeutic resistance [85]. Studies by Khan and Zhang have demonstrated that pharmacological inhibition of SIRT1 restores p53 and NF-κB acetylation, enhances immune infiltration, reduces metastatic spread, and sensitizes NSCLC cells to chemotherapy [105]. Clinically, elevated SIRT1 expression in NSCLC correlates with a poor response to immunotherapy and shortened patient survival, underscoring its role as a redox-driven regulator of tumor maintenance [105]. Notably, the functional roles of SIRT1 appear to differ among NSCLC histological subtypes. In adenocarcinoma, which often features EGFR or KRAS mutations and relies heavily on mitochondrial oxidative metabolism, SIRT1-driven deacetylation of PGC-1α and FOXO3 plays a central role in maintaining mitochondrial function and redox balance [106,107,108]. These actions support metabolic flexibility and resistance to oxidative stress. In contrast, squamous cell carcinoma, commonly linked to chronic smoking and DNA damage, is more dependent on inflammatory signaling pathways. In this context, SIRT1-mediated suppression of NF-κB activity via deacetylation at K310 may serve as a critical mechanism to restrain SASP-related inflammation and limit paracrine senescence [79,109]. These subtype-specific patterns suggest that SIRT1 supports tumor progression through distinct molecular axes depending on the underlying redox and genetic landscape, warranting tailored therapeutic approaches for each histological subtype. These observations underscore the central role of SIRT1 in the immune evasion and metabolic adaptation of NSCLC cells. However, most mechanistic studies have relied on xenografts, which lack intact immune–tumor interactions. In addition, subtype-specific evidence suggests distinct functions in adenocarcinoma and squamous carcinoma, highlighting context dependency [110,111]. Thus, future studies should use patient-derived and immunocompetent models to clarify whether SIRT1 inhibition can synergize with immunotherapy and define subtype-tailored strategies.

In gastrointestinal cancer, SIRT1 enhances tumor cell survival by promoting redox homeostasis, mitochondrial function, and resistance to metabolic stress. SIRT1 regulation of p53-driven transcription is a recurring mechanism across GI tumors that contributes to redox homeostasis and resistance to stress-induced apoptosis [112]. Furthermore, deacetylation of PGC-1α promotes mitochondrial biogenesis and oxidative phosphorylation, ensuring adequate ATP production while minimizing oxidative stress. Under nutrient-deprived and chemotherapeutic conditions, SIRT1 activates autophagy-related genes, such as LC3 and Beclin-1, supporting cellular adaptation and survival [113,114]. Preclinical studies have shown that pharmacological inhibition of SIRT1 restores p53 acetylation and sensitizes gastrointestinal tumor cells to oxidative stress-induced apoptosis, suggesting that SIRT1 acts as a redox-responsive regulator of tumor progression in gastrointestinal malignancies [56,112]. Collectively, these findings suggest that SIRT1 is a redox-responsive regulator of survival in gastrointestinal cancer. However, the current evidence is predominantly preclinical, with limited patient-based validation. Moreover, contradictory reports have suggested that SIRT1 exerts protective effects in early tumorigenesis by preserving genomic stability. These discrepancies emphasize the need for stage- and tissue-specific analyses to determine whether SIRT1 inhibition is beneficial in advanced GI cancers but potentially detrimental to early lesions [49].

SIRT1 inhibitors have emerged as promising therapeutic agents for disrupting cancer cell survival and promoting apoptosis [48]. In addition to modulating the cell cycle and apoptotic signaling, many of these inhibitors impair redox homeostasis by restoring the acetylation of transcription factors, such as p53 and FOXO. This leads to increased oxidative stress and sensitizes cancer cells to ROS-mediated cytotoxicity [59]. Several compounds have been developed to target SIRT1, each with a unique mechanism of action and varying degrees of success in preclinical and clinical studies. Below, we discuss the key SIRT1 inhibitors that have shown potential for cancer therapy.

SIRT1 inhibitors are gaining attention as innovative approaches to cancer therapy. SIRT1 inhibition promotes apoptosis, enhances sensitivity to chemotherapy, and reduces chemoresistance in various cancers. For example, Tenovin-6 induces apoptosis by increasing p53 acetylation, whereas EX-527 exhibits significant anti-cancer effects in ovarian and breast cancer models [117,119]. Several SIRT1 inhibitors, such as EX-527 and nicotinamide, are currently in clinical trials and show promising outcomes in reducing cancer cell proliferation and improving chemotherapy response [126,127]. In addition, SIRT1 inhibitors impair redox homeostasis by restoring the acetylation of transcription factors, such as p53 and FOXO. This results in elevated ROS levels and increased sensitivity to oxidative stress in cancer cells, thereby enhancing their vulnerability to therapeutic interventions. Such redox-disruptive mechanisms help overcome therapeutic resistance, particularly in tumors that rely on adaptive antioxidant responses [59]. More selective and potent SIRT1 inhibitors are currently under development and are expected to further expand their therapeutic potential. Despite the promising results from preclinical and early clinical studies, several challenges remain in the translation of SIRT1 inhibitors into clinical practice [128,129]. First, because SIRT1 also regulates redox balance in normal cells, systemic inhibition may disrupt physiological oxidative homeostasis, potentially leading to off-target toxicity, especially in high-turnover tissues. Second, SIRT1 plays dual roles in cancer, acting as a tumor suppressor in certain contexts (e.g., early-stage cancers or low stress environments) and as a tumor promoter in other contexts (e.g., advanced or redox-stressed tumors). This context-dependent nature complicates broad clinical applications and highlights the need to identify precise molecular signatures that can predict therapeutic benefits. Finally, tumor heterogeneity may lead to variable responses or resistance to SIRT1-targeted therapies [49,96,130]. Mechanisms, such as compensatory activation of alternative NAD⁺-dependent pathways or upregulation of parallel antioxidant systems (e.g., NRF2), may limit therapeutic efficacy. Therefore, rational patient stratification and development of reliable biomarkers are essential for optimizing clinical outcomes. However, translating these findings into clinical benefits remains challenging [131]. First, the dual role of SIRT1 as both a tumor promoter and suppressor, depending on the cellular context, complicates its therapeutic application. Second, most evidence arises from preclinical models that may not fully recapitulate patient tumor heterogeneity or immune–tumor interactions. Third, the lack of validated biomarkers for patient stratification limits the precise identification of patients who will benefit most from SIRT1 inhibition. Finally, systemic toxicity remains a concern, as SIRT1 contributes to redox balance and genomic stability in normal tissues [49,132].

Future research into SIRT1 inhibitors has substantial potential for the development of more targeted and effective cancer therapies. Large-scale clinical trials are required to confirm the efficacy and safety of SIRT1 inhibitors in different cancer types. A deeper understanding of how SIRT1 regulates cancer cell survival, proliferation, migration, and drug resistance is essential to optimize therapeutic strategies. In particular, investigating how SIRT1 modulates redox homeostasis and oxidative stress adaptation in cancer cells is critical because redox regulation is closely linked to senescence evasion, metabolic reprogramming, and therapeutic resistance [46,96]. Combining SIRT1 inhibitors with existing cancer therapies, such as immune checkpoint inhibitors, may yield synergistic effects and provide personalized treatment options based on cancer-specific characteristics. Advances in drug delivery technologies may further enhance the specificity and clinical utility of SIRT1 inhibitors by reducing off-target effects and improving therapeutic indices. Importantly, because SIRT1 also contributes to the redox balance and genomic stability in healthy cells, indiscriminate inhibition can result in undesirable toxicity [133]. Therefore, the selective targeting of SIRT1 in cancer cells through tumor-specific delivery systems, context-dependent inhibitors, or exploitation of cancer-specific redox vulnerabilities should be prioritized to maximize therapeutic benefits while minimizing harm to normal tissues. Future research should prioritize the development of cancer-selective SIRT1 inhibitors, the integration of biomarker-driven clinical trial designs, and exploration of rational combination strategies with chemotherapy, immunotherapy, or metabolic modulators [48,133]. Advances in drug delivery, such as nanoparticle-based systems or tumor-targeted prodrugs, may improve specificity and reduce systemic toxicity. Addressing resistance mechanisms such as compensatory NAD⁺ pathways or NRF2 activation is also essential for long-term efficacy [96,128].