The role of hepatic SIRT1: From metabolic regulation to immune modulation and multi-target therapeutic strategies

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic liver disorder globally, with a rising incidence linked to metabolic syndrome. Its pathogenesis involves a complex interplay of lipid metabolic dysregulation, insulin resistance, oxidative stress, chronic inflammation, and gut-liver axis disruption. Despite recent advances such as Resmethron for advanced metabolic-associated steatohepatitis (MASH), early-stage interventions remain limited. This review highlights silent information regulator 1 (SIRT1), an NAD⁺-dependent deacetylase, as a central regulator in MASLD, orchestrating metabolic homeostasis, immune modulation, and inter-organ communication.

Structure and Regulatory Mechanisms of SIRT1
SIRT1, a class III histone deacetylase, is highly expressed in metabolically active tissues. Its catalytic core facilitates deacetylation of both histone and non-histone substrates, including PGC-1α, FOXO, NF-κB, and p53. SIRT1 activity is modulated by the NAD⁺/NADH ratio, AMPK signaling, and miRNAs such as miR-34a, which is often elevated in metabolic disorders. Protein interactions with regulators like DBC1 and AROS further fine-tune its function, positioning SIRT1 as a key metabolic and epigenetic sensor.

Multifactorial Pathogenesis of MASLD
MASLD progression is driven by lipid overload, insulin resistance, oxidative stress, and immune activation. Free fatty acids promote hepatic triglyceride accumulation, while mitochondrial dysfunction elevates reactive oxygen species (ROS), triggering inflammation and Kupffer cell activation. Gut dysbiosis and barrier impairment facilitate endotoxin translocation, activating TLR4/NF-κB signaling and perpetuating a vicious cycle of metabolic and inflammatory injury.

Mechanistic Roles of SIRT1 in MASLD
Cell Type Specificity: SIRT1 exhibits cell-specific functions in hepatocytes, Kupffer cells (KCs), hepatic stellate cells (HSCs), and immune cells, necessitating precise therapeutic targeting.

Lipid Metabolism Regulation: SIRT1 inhibits lipogenesis by deacetylating SREBP-1c and promotes fatty acid oxidation via PGC-1α/PPARα activation, thereby reducing hepatic steatosis.

Insulin Sensitivity and Glucose Metabolism: Through the LKB1/AMPK and FOXO1 pathways, SIRT1 suppresses gluconeogenesis and enhances insulin signaling, improving systemic glucose homeostasis.

Inflammation and Immune Modulation: SIRT1 deacetylates NF-κB p65, inhibiting pro-inflammatory cytokine release. It also regulates T-cell differentiation, promotes Treg function, and modulates neutrophil recruitment, maintaining hepatic immune balance.

Pyroptosis Regulation: By suppressing NLRP3 inflammasome activation and gasdermin D cleavage, SIRT1 mitigates hepatocyte pyroptosis and inflammatory liver damage.

Autophagy and ER Stress Alleviation: SIRT1 enhances autophagic flux and lipophagy via FOXO and AMPK/mTOR pathways, while deacetylating ER stress mediators to reduce unfolded protein response-induced apoptosis.

Mitochondrial Homeostasis and ROS Control: SIRT1 activates antioxidant pathways via FOXO3a and Nrf2, promotes mitophagy, and supports mitochondrial biogenesis through PGC-1α, though its effects are context-dependent.

Gut-Liver Axis and Gut Microbiota: SIRT1 strengthens intestinal barrier integrity by upregulating tight junction proteins, modulates gut microbiota composition, and suppresses LPS-induced inflammation, thereby protecting the liver from gut-derived insults.

Therapeutic Potential of SIRT1 Activators
Natural Product Activators: Resveratrol, curcumin, quercetin, and procyanidins enhance SIRT1 activity, improving lipid metabolism, reducing inflammation, and restoring gut-liver axis function. However, poor bioavailability limits their clinical utility.

Synthetic Small-Molecule Activators: Compounds like SRT1720 and SRT2104 show promise in preclinical models by enhancing SIRT1-mediated metabolic and anti-inflammatory pathways, though issues of tissue specificity and toxicity remain.

NAD⁺ Precursors: Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) boost NAD⁺ levels, indirectly activating SIRT1 and improving mitochondrial function and insulin sensitivity.

Challenges and Future Perspectives
The translational application of SIRT1-targeted therapies faces challenges, including cell-type specificity, optimal dosing, and potential off-target effects. Future research should focus on spatiotemporal mapping of SIRT1 activity, development of tissue-specific delivery systems, and combination therapies leveraging SIRT1’s network-regulating capabilities.

Conclusion
SIRT1 stands at the nexus of metabolic and immune regulation in MASLD, offering a multi-target therapeutic strategy. With continued mechanistic insight and innovative targeting approaches, SIRT1 activation holds significant potential for precision intervention in MASLD.

 

Full text

https://xiahepublishing.com/2310-8819/JCTH-2025-00259

 

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

Follow us on X: @xiahepublishing

Follow us on LinkedIn: Xia & He Publishing Inc.

---

---