In a HFD-induced mouse model of MASLD and Palmitic acid (PA)-treated AML-12 cells, didymin increased SIRT1 expression and directly activated SIRT1, thereby enhancing mitochondrial biogenesis and function, reducing apoptosis, and promoting lipophagy, ultimately alleviating MASLD51. Here, SIRT1 is linked to metabolic dysfunction-associated steatotic liver disease.