SIRT1, the most extensively researched member of the sirtuin family, predominantly localizes in the nucleus. It modulates nucleosome histone acetylation and regulates the functionality of various transcription factors (13). Sirt1 is predominantly localized within the nucleus; however, under specific stimuli, it translocates to the cytoplasm. This protein serves a crucial function in regulating diverse biological processes, including mitochondrial metabolic dysfunction (14), inflammation (15), oxidative stress (16), telomere integrity (17), DNA damage response (18), and autophagy (19).

Systemic Sirt1 knockout mice exhibit markedly elevated mitochondrial dysfunction and increased mortality following AKI compared to their wild-type counterparts (20). SIRT1 mediates the deacetylation of both histone and non-histone proteins, performing a key role in preserving cellular homeostasis. Cytoplasmic cortactin plays a crucial role in the stabilization of the actin cytoskeleton (21). SIRT1 safeguards podocytes and facilitates glomerular repair by promoting the deacetylation of cortactin within the nucleus. This deacetylation process is essential for the translocation of acetylated cortactin to the cytoplasm, thereby preserving the integrity of the actin cytoskeleton. SIRT1 enhances high glucose (HG)-induced epithelial-mesenchymal transition (EMT) by deacetylating the transcription factor Yin Yang 1 (YY1) (22). The acetylation of high-mobility group box 1 (HMGB1) is a pivotal step required for its nuclear export, cytoplasmic translocation, and subsequent extracellular secretion in renal cells, a process that exacerbates the progression of renal diseases. SIRT1 deacetylates lysine residues on HMGB1, attenuating subsequent inflammatory signaling pathways (23). In a model of renal fibrosis, both acetylation and p53 expression were elevated; however, SIRT1 mitigated the advancement of ferroptosis by promoting the deacetylation of p53 (24). In aged mice, SIRT1 expression was significantly reduced compared to young mice (5 weeks old), resulting in increased ECM deposition. SIRT1 overexpression, by deacetylating hypoxia-inducible factor-1α (HIF-1α), effectively mitigated hypoxia-induced reactive oxygen species (ROS) production, mitochondrial dysfunction, and ECM protein accumulation, exerting a protective impact on the tubulointerstitial compartment of aged kidneys (25).

SIRT1 alleviates renal inflammation through the deacetylation of nuclear factor-κB (NF-κB) (26), and enhances renal energy metabolism and oxidative stress response by deacetylating forkhead box protein (FOXO) (27) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). SIRT1 attenuates renal fibrosis through the deacetylation of Smad3 (28), enhances renal hypoxia tolerance through the deacetylation of HIF-1α (25), and protects against apoptosis in resident kidney cells by deacetylating p53 (29). Moreover, recent studies have demonstrated that SIRT1 enhances renal autophagy through the deacetylation of Beclin1 (19), and cooperates with SIRT3 by activating RelB to enhance mitochondrial biogenesis (30). Consistent with these findings, podocyte-specific Sirt1 knockout mice develop renal fibrosis (31), accompanied by disruption of the actin cytoskeleton (21), activation of the NOD-like Receptor Pyrin Domain Containing 3 (NLRP3) inflammasome (32), and mitochondrial dysfunction in podocytes (33). These pathological changes are notably ameliorated in transgenic mice overexpressing SIRT1 in podocytes (34). Notably, several studies have revealed that claudin-1 expression in podocytes is upregulated and correlates with worsened phenotypes in a mouse model of proteinuric nephropathy with proximal tubule-specific SIRT1 knockout, suggesting that SIRT1 plays a role in the crosstalk between glomerular endothelial cells and tubular epithelial cells. Furthermore, evidence indicates that SIRT1 is intimately connected to endocrine signaling pathways (35). Melatonin, a key hormone produced by the pineal gland, is crucial for regulating redox homeostasis, immune responses, and mitochondrial function. Nevertheless, these effects are partially mediated through the activation of SIRT1 (36). SIRT1 plays a multifaceted role beyond deacetylation, encompassing involvement in ubiquitination, phosphorylation and other critical physiological and pathological mechanisms. Specifically, SIRT1 mediates the dephosphorylation and deacetylation of p65 NF-κB and STAT3, thereby attenuating inflammation, oxidative stress, and EMT in diabetic kidney disease (DKD) (37). In a murine model of unilateral ureteral obstruction (UUO), the activation of SIRT1 signaling was correlated with elevated levels of phosphorylated endothelial nitric oxide synthase (eNOS). Furthermore, SIRT1’s interaction with eNOS contributed to ameliorating renal fibrosis, as assessed by fibrosis scoring in the UUO model (38). In diabetic kidney disease, oxidative stress induces SIRT1 ubiquitination, facilitating its degradation. Conversely, inhibiting SIRT1 ubiquitination enhances FoxO3a nuclear translocation and mitigates oxidative stress-induced renal injury in DKD murine models (39).

SIRT6 is a versatile protein that modulates a diverse range of cellular processes. Early studies of its enzymatic activity identified SIRT6 as a mono-ADP-ribosyltransferase and a deacetylase, capable of removing acetyl groups from histone and non-histone substrates alike (40). SIRT6 is defined by its deacetylase activity that is approximately 1000-fold slower than that of other SIRT family members, distinguishing it from its counterparts (41). Notably, the unique structural configuration of SIRT6 facilitates high-affinity binding to NAD⁺ even without the presence of an acetylated substrate. This unique characteristic arises from its diverged zinc-binding domain and a robust single helix that facilitates NAD⁺ binding (41). Characterized by numerous interaction partners and the capacity to catalyze the removal of diverse post-translational modifications, SIRT6 has a critical impact on essential cellular processes, consisting of DNA repair, gene regulation, telomere maintenance, and cell division (42).

SIRT6 also works in synergy with SIRT1, which deacetylates SIRT6 at lysine 33. This deacetylated form of SIRT6 is then anchored to γH2AX, facilitating its retention within the local chromatin and enabling chromatin remodeling (43). SIRT6 possesses three catalytic activities: deacylation, deacetylation and mono-ADP-ribosylation. Among its histone substrates, SIRT6 commonly deacetylates histone H3 at 56 (H3K56) and lysines 9 (H3K9) (44). Sirt6 is essential for telomere integrity, functioning through the deacetylation of histone H3K9, which mitigates telomeric DNA damage and delays the onset of cellular senescence (45). The deacetylation of histone H3K56 modulates the expression of β-catenin target genes, suppresses transcription of genes associated with fibrosis, and influences renal interstitial fibrosis (46). Additionally, Sirt6 extends its deacetylase activity to non-histone substrates within both the nucleus and cytoplasm, targeting proteins such as members of the p53, FOXO family, NAMPT and Smad (47). SIRT6 regulates renal interstitial fibrosis through the deacetylation of runt-related transcription factor 2 (Runx2), facilitating its nuclear export, and triggering the activation of the ubiquitin-proteasome pathway, which results in Runx2 degradation. This process ultimately suppresses vascular calcification in chronic kidney disease (CKD) (48). Moreover, Sirt6 undergoes acetylation by Sirt1, and the two proteins function in concert to preserve organismal homeostasis (49). In the glomeruli of individuals with hypertensive nephropathy, elevated DNA double-strand breaks (DSBs) are associated with reduced Sirt6 expression. Conversely, Sirt6 overexpression, which upregulates nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), suppresses angiotensin II(Ang II)-induced ROS production and DNA DSBs, thereby playing a crucial role in mitigating oxidative DNA damage triggered by Ang II stimulation (50). Renal interstitial fibrosis represents a prevalent pathological feature of CKD. Overexpression of Sirt6 mitigates the progression of this condition in CKD by targeting homeodomain-interacting protein kinase 2, as demonstrated by decreased collagen deposition and downregulation ofα-smooth muscle actin and collagen I (51). Progressive epithelial-mesenchymal transition in the kidneys of db/db mice is linked to the downregulation of Sirt6, with diminished Sirt6 levels contributing to worsening renal pathology, including tubular injury. Further investigations have shown that Sirt6 directly interacts with Smad3, where it deacetylates Smad3, thereby inhibiting its transcriptional activity and nuclear accumulation, offering protection against renal injury in diabetic kidney disease (52). Sirt6 also interacts with saturated fatty acids, particularly palmitic acid, facilitating their export from the nucleus. It induces the deacetylation of acyl-CoA synthetase long-chain 5, thereby enhancing FAO. These findings suggest that Sirt6 extends its metabolic regulatory functions beyond the nucleus, offering new insights into its role in kidney disease (53).

SIRT7 is the sole sirtuin localized within the nucleolus, where its deacetylase activity is essential for the transcription of ribosomal DNA. Sirt7 associates with and deacetylates HMGB1, prompting its translocation to the nucleus and enhancing its role in DNA damage repair. Additionally, Nucleophosmin (NPM), another substrate of Sirt7, undergoes deacetylation by Sirt7, which facilitates its relocation from the nucleolus to the nucleoplasm. In the nucleoplasm, deacetylated NPM associates with ubiquitin ligase, thereby inhibiting p53 ubiquitination and degradation, leading to cell cycle arrest and the preservation of DNA damage repair mechanisms (47). Following DNA damage, ataxia-telangiectasia mutated (ATM) is activated by autophosphorylation; evidence suggests that ATM deacetylation is necessary for its subsequent dephosphorylation. Sirt7 has been shown to deacetylate ATM, thereby limiting its persistent phosphorylation and activation, and consequently facilitating DNA damage repair (54). Conversely, the absence of Sirt7 suppresses NF-κB phosphorylation, diminishes p53 nuclear translocation, and mitigates renal inflammation and tubular damage (55). Sirt7 directly downregulates NF-κB expression, reducing cisplatin-induced acute kidney injury and attenuating apoptosis in renal tubular epithelial cells (56). Overexpression of Sirt7, which counters the observed reduction in Sirt7 levels during hypertensive kidney injury, enhances Krüppel-like factor 15/Nrf2 signaling and significantly mitigates Ang II-induced ferroptosis, renal dysfunction, interstitial fibrosis, and epithelial-mesenchymal transition in mice with hypertensive. These findings suggest that Sirt7 represents a potential therapeutic target for treating hypertensive kidney injury (57). Furthermore, Sirt7-deficient mice exhibit protection against AKI, characterized by phosphorylation of p65 and decreased nuclear translocation, along with diminished inflammatory infiltration of renal cells. This protective impact is further substantiated by diminished proteinuria and decreased markers of renal tubular damage (58).

SIRT2 is primarily localized in the cytoplasm, exhibiting deacetylase and demyristoylase activities. It holds significant importance in regulating NF-κB signaling, microtubule dynamics, and adipocyte differentiation through the deacetylation of specific substrates, including p65, alpha-tubulin and the transcription factor FOXO1, respectively (59). Moreover, various proteins, including homeobox transcription factor 10 and 14-3-3 β/γ, are recognized as binding partners of SIRT2, though they are not substrates for its deacetylase activity (60). Additionally, SIRT2 has been implicated in the suppression of basal autophagy through its interaction with autophagy-related gene 7 (61). The diversity of SIRT2 substrates and conjugates highlights its multifaceted role in cellular function. SIRT2 influences metabolic processes within the cytoplasm by responding to NAD levels and regulating proteins integral to metabolic homeostasis, including phosphoglycerate kinase and aldolase. Initially identified as a tubulin deacetylase, SIRT2 has since been shown to interact with and regulate a wide array of both non-histone and histone protein substrates (62). Sirt2 modulates the acetylation of p53 at lysine 382, stabilizing p53 within the nucleus, promoting its transcriptional activity, and exerting a crucial function in the DNA damage response (63). Sirt2 is suggested to associate with the BRCA1-BARD1 complex, deacetylating a conserved lysine residue within the complex to facilitate BRCA1-BARD1 heterodimerization. This modification enhances the complex’s localization to regions of DNA damage, thereby promoting efficient homologous recombination (64). Sirt2 plays a critical role in modulating proinflammatory responses. Its overexpression intensifies cisplatin-induced cellular apoptosis, renal injury, and inflammation, while also enhancing the activation of c-Jun N-terminal kinase (JNK) phosphorylation and p38 (65). Conversely, Sirt2 deficiency mitigates lipopolysaccharide-induced neutrophil and macrophage infiltration, leading to improved renal function (66). During renal ischemia/reperfusion, Sirt2 activation leads to the binding and deacetylation of FOXO3a, facilitating its translocation to the nucleus, which in turn activates caspase-3 and caspase-8, thereby initiating apoptosis. Conversely, inhibition of Sirt2 effectively reverses these processes (67). Sirt2 activity is implicated in the induction and expansion of renal fibroblast activity, in contrast, suppression of Sirt2 attenuates renal fibrosis progression and presents a promising therapeutic strategy for managing CKD (68).

SIRT3 is predominantly localized within the mitochondrial matrix and serves as the principal regulator of the mitochondrial acetylome, distinguishing it from other mitochondrial sirtuins including SIRT4 and SIRT5 (69). As a representative member of the SIRT family, SIRT3 possesses a conserved enzymatic core (amino acids 126-399) that mediates deacetylation in a (NAD⁺)- dependent manner (70). During the initial stages of renal fibrosis, diminished Sirt3 expression is associated with increased mitochondrial acetylation, and Sirt3-knockout mice display a susceptibility to mitochondrial protein hyperacetylation, leading to exacerbated renal fibrosis (71). Impairment of fatty acid oxidation (FAO) is a key contributor to the progression of renal fibrosis. AKI mice display marked FAO disruption and lipid accumulation, accompanied by elevated ROS production. Moreover, Sirt3 deletion exacerbates FAO dysfunction and renal injury in AKI mice. Further mechanistic investigations suggest that Sirt3 may regulate FAO, facilitate repair, and attenuate renal damage through Adenosine 5’-monophosphate (AMPK) activation (72). Evidence shows that even under normal conditions, SIRT3 knockout mice display pronounced hyperacetylation of various mitochondrial proteins (47). In the context of kidney disease, SIRT3 serves a pivotal function in regulating fatty acid oxidation, deacetylating p53 and superoxide dismutase 2 (SOD2), and mitigating renal damage caused by oxidative stress (73). SIRT3 also deacetylates key proteins such as liver kinase B1(LKB1), SOD2, Cyclophilin D(CypD), Mitochondrial Fusion Protein 2(Mfn2), and PGC-1α to inhibit the opening of the mitochondrial permeability transition pore (mPTP), thereby enhancing mitochondrial function and dynamics (74). Notably, SIRT3 has been implicated in the regulation of early renal development. Studies have shown, in AKI mouse models, SIRT3 knockout exacerbates mitochondrial dysfunction (75), oxidative stress (74), renal impairment, apoptosis, and fibrosis (76). SIRT3 deficiency has been reported to facilitate the mesenchymal transition of tubular epithelial cells, contributing to fibrosis in diabetic kidney disease (77). Additionally, like SIRT1, melatonin has been shown in some studies to activate SIRT3 and ameliorate AKI (78). Recent research has also identified sex-related differences in SIRT3’s susceptibility to ischemia-reperfusion injury (79). Moreover, SIRT3 deficiency can enhance abnormal glycolysis, with glycolytic metabolites downregulating SIRT3 and triggering EMT, thereby exacerbating kidney fibrosis (80). Notably, SIRT3 has also been found to mitigate fibrosis in diabetic kidney disease through the Fibroblast Growth Factor Receptor 1 pathway (81).

Sirt4 modulates the posttranslational modifications of diverse proteins through aliphatic amidase activity, deacetylation and Adenosine Diphosphate (ADP)-ribosylation/nucleotidyltransferase functions, influencing a wide range of biological processes (82). Sirt4 promotes ADP ribosylation and inhibits glutamate dehydrogenase activity, subsequently blocking the conversion of glutamate to α-ketoglutarate in the tricarboxylic acid cycle (83). Furthermore, Sirt4 deficiency results in reduced expression and functionality of the glutamate transporter (84), a factor that may play a more critical role than Sirt4’s deacetylation activity. Sirt4 plays an essential role in preserving mitochondrial function and has been implicated in the development of metabolic disorders, such as diabetic kidney disease. In DKD, Sirt4 mRNA and protein expression are significantly diminished in podocytes exposed to glucose stimulation, with the reduction occurring in a concentration-dependent fashion. Sirt4 deficiency triggers the NLRP3 inflammasome and activation of NF-κB signaling, thereby worsening renal injury (85). Elevated FOXO1 levels and reduced Sirt4 expression have been observed in db/db mice, with FOXO1 overexpression further suppressing Sirt4 and aggravating mitochondrial damage. In contrast, FOXO1 gene silencing enhanced Sirt4 expression and partially recovered mitochondrial function (82).

Sirt5 shows a high affinity for negatively charged acyl groups, including glutarate, succinate, and malonate. It primarily catalyzes lysine acylation but exhibits desuccinylase and deglutarylase activities, with limited deacetylase activity (86). The regulation of Sirt5 is influenced by two key molecules: PGC-1α overexpression increases Sirt5 levels, while AMPK activation decreases its expression (87). Ribose-5-phosphate is essential for nucleotide biosynthesis, and studies have shown that Sirt5 knockdown impairs ribose-5-phosphate production, resulting in persistent and irreversible DNA damage (88). P53 plays an essential role in maintaining genomic stability. Following DNA damage, Sirt5 facilitates the desuccinylation of p53 at lysine 120, consequently inhibiting its activity (89). Increased Sirt5 expression mitigates mitochondrial dysfunction by promoting AMPK phosphorylation, as demonstrated by the preservation of mitochondrial structure, restoration of ATP levels, and deceleration of AKI progression (90). Moreover, Sirt5 plays a crucial role in preserving FAO homeostasis in mitochondria and peroxisomes of renal tubular epithelial cells (RTECs), thereby conferring protection AKI-induced damage (91).

The increased vulnerability of aging kidneys to ischemia/reperfusion (I/R) injury suggests that sirtuins may contribute to the pathogenesis of I/R-induced renal damage. Overexpression of SIRT1 has been linked to increased resistance against kidney injury induced by I/R, whereas the loss of a single SIRT1 allele exacerbated renal damage following I/R (98). SIRT1 mitigated kidney injury caused by I/R by activating antioxidant pathways, including the nuclear factor erythroid Nrf2/HO-1 signaling (99), while also reducing p53 expression and inhibiting apoptosis (98). SIRT1 further mitigated ischemia/reperfusion-induced kidney injury by promoting mitochondrial biogenesis. In the kidney, Ischemia/reperfusion (I/R) injury was observed to upregulate SIRT3 expression. Considering SIRT3’s primary localization within the mitochondrial matrix, it is likely that SIRT3 influences the progression of I/R-induced kidney injury, particularly through its impact on mitochondrial dysfunction. Overexpression of SIRT3 has been demonstrated to offer renal protection by inhibiting superoxide production (100). Diminished SIRT3 expression correlated with heightened severity of I/R-induced renal injury; however, reestablishing SIRT3 levels mitigated this damage by regulating mitochondrial homeostasis via the AMPK/PGC-1α signaling pathway (101). A recent study revealed elevated SIRT5 expression in both peroxisomes and mitochondria of proximal tubular cells. However, unlike other sirtuins, SIRT5 exhibited a divergent role in I/R-induced kidney injury, where its loss conferred renoprotective effects. The proposed mechanism involved the shift of fatty acid oxidation from mitochondria to peroxisomes, regulated by SIRT5. Conversely, SIRT6 expression exhibited an inverse correlation with the severity of hypoxia-induced damage and inflammation in tubular cells (102). The distinct roles of each sirtuin in I/R-induced renal injury warrant further investigation to elucidate their mechanisms and therapeutic potential. In an IRI model of AKI, the deacetylation of PGC1α by SIRT1 was essential for promoting mitochondrial biogenesis and oxidative respiration, thereby sustaining the energy supply necessary for tubular injury after repair (103). Correspondingly, silencing SIRT1 markedly worsened kidney IRI (98).

Cisplatin-induced renal injury results in decreased mitochondrial quantity and functionality, coupled with increased ROS production. Due to the pivotal role of sirtuins in mitochondrial biogenesis and maintenance, their function has been more thoroughly investigated in the context of cisplatin-induced AKI compared to other etiologies of AKI. Transgenic mice with renal tubule-specific overexpression of SIRT1 exhibited reduced functional and histological indicators of kidney injury following cisplatin administration. This protection was linked to a decrease in cisplatin-induced apoptosis and oxidative stress (104). Recent studies have highlighted the renoprotective function of SIRT3 in cisplatin-induced acute kidney injury through its regulation of mitochondrial dysfunction. In mice models, the absence of SIRT3 function exacerbated renal impairment following cisplatin administration. Conversely, pharmacological activation of SIRT3 alleviated cisplatin-induced renal injury in wild-type mice, but failed to yield the same protective effects in SIRT3-deficient mice. Cisplatin-induced downregulation of SIRT3 led to mitochondrial fragmentation in tubular cells, whereas the restoration of SIRT3 activity counteracted the damage and maintained mitochondrial structural integrity (74). Further studies have reinforced the renoprotective effects of SIRT3 in alleviating cisplatin-induced AKI by modulating mitochondrial dysfunction (105, 106). Among the nuclear sirtuins, SIRT6-deficient mice demonstrated exacerbated cisplatin-induced renal injury. Conversely, SIRT6 mitigates renal apoptosis and inflammation through the deacetylation of H3K9 and the suppression of extracellular signal-regulated kinase (ERK)-1/2 signaling (107).

Contrary to SIRT1, SIRT3, and SIRT6, the deficiency of SIRT2 and SIRT7, rather than their overexpression, notably alleviated cisplatin-induced AKI. This protective effect was achieved by reducing apoptosis and inflammation by modulating JNK and p38 pathways (65, 108). Conflicting evidence exists concerning the function of SIRT5 in cisplatin-induced AKI. One investigation involving renal tubular cells demonstrated that SIRT5 overexpression mitigated cisplatin-induced apoptosis and mitochondrial damage by modulating the B-cell lymphoma 2 (Bcl-2) expression and Nrf2/HO-1 pathway (109). Conversely, another investigation revealed that the absence of SIRT5 function in murine models markedly enhanced renal function and reduced tubular injury in cisplatin-induced AKI via the promotion of peroxisomal fatty acid oxidation in proximal renal tubules (91). The precise function of SIRT5 in cisplatin-induced AKI remains to be fully elucidated.

The protective effects of sirtuins in mitigating sepsis-induced AKI were linked to diminished inflammasome activation and augmented autophagic processes. Nevertheless, in line with observations in cisplatin-induced AKI, the deficiency of SIRT2 in murine models led to enhanced renal function and reduced tubular damage following lipopolysaccharide exposure (65). The role of sirtuins has been further clarified in contrast-induced nephropathy (CIN) (110), which is the third leading cause of hospital-acquired AKI. Reports indicate that oxidative stress, driven by superoxide generation and associated pathways, contributes to the pathogenesis of CIN, with its effects regulated by the expression levels of sirtuins.

Considering the pivotal involvement of sirtuin activation in aging-associated pathologies, particularly renal disorders, numerous sirtuin-targeting compounds with high binding affinities have been developed. Notable examples include SRT1720, SRT3025, and MDL-800. SRT1720, a Sirt1 activator, has been shown to decrease p65 acetylation, promote autophagic processes in high glucose-induced podocyte EMT, alleviate renal fibrosis, and restore kidney function (172). SRT3025, another Sirt1 activator, has been documented to counteract the elevation of collagen synthesis induced by TGF-β1, mitigate glomerulosclerosis and tubulointerstitial fibrosis, and ameliorate both the decline in glomerular filtration rate and the severity of proteinuria (173). SRT2183, another Sirt1 activator, has been shown to enhance the resilience of renal medullary interstitial cells to oxidative stress, while reducing apoptosis and fibrosis in a murine model of UUO-induced kidney injury. This effect is mediated by Sirt1-driven upregulation of cyclooxygenase-2 (COX2) expression in renal medullary interstitial cells (153). MDL-800, a Sirt6 activator, has been reported to alleviate tubulointerstitial inflammation and fibrosis in UUO-induced models. In vitro studies demonstrated that MDL-800 suppresses TGF-β1-induced myofibroblast activation and ECM production by modulating Sirt6-dependent β-catenin acetylation and regulating the TGF-β1/Smad signaling pathway (174).

Apart from sirtuin activators, a range of sirtuin inhibitors has been developed to treat various renal pathologies. Research has established the role of Sirt2 in driving inflammation and renal fibrosis, leading to the development of Sirt2 inhibitors, including AK-1 and AGK2. Pre-administration of the Sirt2 inhibitor AGK2 before renal ischemia-reperfusion notably diminished the incidence of apoptotic renal tubular cells and alleviated associated ultrastructural damage (67). Sirt2 activity appears to play a role in the activation and proliferation of renal fibroblasts. The Sirt2 inhibitor AGK2 effectively suppressed fibroblast activation and, to a reduced extent, cell proliferation in a dose- and time-dependent manner, as indicated by decreased expression levels of collagen I, α-smooth muscle actin, and fibronectin (68). AK-1, another Sirt2 inhibitor, enhances Nrf2 activity while suppressing JNK signaling, thereby mitigating oxidative stress (178).