Hepatic is presented as a network regulator of metabolism, inflammation, and organ-axis signaling in .
Evidence
This review synthesizes mechanistic and translational studies on SIRT1 regulation of lipid remodeling, mitochondrial quality control, autophagy-endoplasmic reticulum stress balance, immune polarization, and gut-liver interactions in MASLD.
Caveat
The therapeutic case remains bounded by clinical translation problems, especially tissue-selective delivery, spatiotemporal specificity, and dynamic dosage optimization of SIRT1 activators.
Simplified
Metabolic dysfunction-associated steatotic liver disease (), the most common chronic liver disorder worldwide, results from multidimensional network dysregulation involving lipid metabolism imbalance, insulin resistance, oxidative stress, chronic inflammation, and gut-liver axis disruption. Silent information regulator 1 (), an NAD-dependent deacetylase, functions as a central regulator of metabolic homeostasis and a key mediator in immune microenvironment remodeling and inter-organ communication. This review systematically describes the multi-target mechanisms of SIRT1 in MASLD pathogenesis through its regulation of critical factors, including peroxisome proliferator-activated receptor gamma coactivator 1-α, Forkhead Box O, and nuclear factor kappa-light-chain-enhancer of activated B cells, which govern hepatocyte lipid remodeling, mitochondrial quality control, autophagy-endoplasmic reticulum stress balance, and Kupffer cell/T cell polarization. This work introduces, for the first time, the concept that SIRT1 mediates systemic regulation of MASLDcoordinated "metabolism-inflammation-organ axis" interactions. Recent studies indicate that natural compounds (e.g., resveratrol, curcumin) improve gut-liver barrier function through microbiota-SIRT1 interactions, while synthetic activators (SRT1720) and NADprecursors (NMN) enhance hepatocyte antioxidant capacity and fatty acid β-oxidation. This innovative analysis highlights the spatiotemporal specificity of various SIRT1 activators, emphasizing that tissue-selective delivery and dynamic dosage optimization are crucial for overcoming clinical translation challenges. By integrating mechanistic and translational insights, this review provides a novel foundation for precision intervention strategies targeting SIRT1 network reprogramming. + + via
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