This study investigated a novel gut microbiota-derived post-translational modification — lysine phenylacetylation (Kpaa) — generated via the phenylalanine/phenylacetic acid (PAA) pathway, examining its effects on hepatic mitochondrial function, insulin signaling, and its regulation by the deacetylase SIRT3 in mouse models of high-fat-diet obesity and in human adults with obesity/MASH.
PAA elevated hepatic Kpaa levels in obese mice, disrupted mitochondrial function, and impaired insulin signaling; specifically, K481paa of HSP60 triggered the mitochondrial unfolded protein response. SIRT3 reversed this modification, and hepatic SIRT3 levels were negatively correlated with Kpaa levels in adults with obesity and MASH.
Causal directionality in humans is unclear due to the correlational design of the human data; the study relies heavily on mouse HFD models, which may not fully recapitulate human MASLD/MASH; the proteome-wide breadth of Kpaa substrates identified warrants further functional validation.
Gut microbiota-derived phenylacetic acid may drive liver disease progression through lysine phenylacetylation of mitochondrial proteins, with SIRT3 as a potential therapeutic target. Clinicians managing MASLD/MASH patients should watch for emerging therapies aimed at the PAA–SIRT3–mitochondrial axis.
