Tissue fibrosis, driven by chronic inflammation and degeneration, leads to progressive organ dysfunction. While significant advancements have been made, effective therapies remain limited. Lactylation, a newly recognized post-translational modification (PTM), has attracted attention in cellular regulation. However, the precise mechanisms through which lactylation influences fibrosis remain poorly understood. In this Review, we integrate current insights into the origin, molecular mechanisms, and dynamic regulation of both histone and non-histone lactylation, with a particular focus on its mechanistic roles in tissue fibrosis. Lactylation acts as a metabolic–epigenetic interface, linking altered cellular metabolism to chromatin remodeling, transcriptional reprogramming, and activation of fibrosis-related signaling networks. Through these processes, lactylation exerts context-dependent and organ-specific effects in fibrotic diseases of the liver, kidney, lung, skin, and other tissues. Notably, its regulatory influence extends beyond non-malignant fibrotic conditions to encompass tumor-associated stromal fibrosis and fibrogenic remodeling during post-injury tissue repair. Moreover, this Review highlights the therapeutic potential of targeting both histone and non-histone lactylation in fibrosis and explores its crosstalk with other PTMs, including acetylation and methylation. Lactylation represents a critical metabolic–epigenetic axis in the initiation and progression of tissue fibrosis. Targeting lactylation—either by modulating specific lactylation sites or regulating lactatemetabolizing key enzymes—offers an effective approach to suppress fibrosis progression and provides a foundation for the development of precision antifibrotic therapies.
Qiu et al. (Thu,) studied this question.
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