Protein lactylation in metabolic dysfunction-associated steatotic liver disease: a mechanistic review

TL;DR

This review explores how protein lactylation, a new type of chemical modification, influences liver disease progression and could lead to new treatments.

Contribution

The paper introduces a novel conceptual framework linking protein lactylation to MASLD progression and potential precision therapies.

Findings

Protein lactylation connects metabolic changes to liver disease progression.

Dysregulation of lactylation occurs in hepatocytes, hepatic stellate cells, and immune cells during MASLD.

Targeting the lactate-lactylation-gene expression axis may offer new therapeutic strategies.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder with limited therapeutic options. While its pathogenesis is complex, the underlying molecular drivers remain incompletely understood. Recently, protein lactylation, a novel lactate-derived post-translational modification (PTM), has emerged as a key regulator linking metabolic reprogramming to cellular function. This review elucidates the pivotal roles of protein lactylation throughout the progression of MASLD, from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma, establishing a conceptual framework centered on the “lactate-lactylation-gene expression” axis and examining its dysregulation across hepatocytes, hepatic stellate cells, and immune cells throughout MASLD. Furthermore, we discuss emerging therapeutic strategies targeting the axis, aiming to provide a theoretical foundation for the development of precision medicine for MASLD.

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