TRIM68 exacerbates sepsis-induced liver injury by inhibiting TIP60-dependent autophagy

Background: Sepsis-induced liver injury (SILI) is a major contributor to mortality in critically ill patients, yet the temporal regulation and functional significance of autophagy in SILI remain poorly defined. Defining the dynamic changes in autophagy and the underlying molecular mechanisms is therefore essential for the development of effective therapies. Methods: We integrated public transcriptomic datasets from human and murine SILI with in vivo and in vitro experimental models to characterize the dynamic regulation of autophagy and identify key regulatory factors. Genetic gain- and loss-of-function approaches targeting tripartite motif containing 68 (TRIM68) were combined with cecal ligation and puncture (CLP) mouse models and LPS-stimulated hepatocytes. These methods were coupled with molecular, biochemical, and imaging analyses, including qRT‒PCR, Western blotting, immunofluorescence, transmission electron microscopy, ELISA, CUT-Tag, coimmunoprecipitation, and ubiquitination assays, to elucidate the underlying mechanisms. Results: Autophagy was dynamically regulated during SILI, with early activation followed by a decrease that coincided with aggravated liver injury and inflammation. Enhancing autophagy significantly alleviated hepatic injury and inflammatory responses. Integrative analyses identified TRIM68 as a conserved autophagy-associated regulator across human and murine SILI. Loss of TRIM68 expression enhanced autophagic flux and reduced proinflammatory cytokine production. Mechanistically, TRIM68 loss stabilized TIP60 by reducing its ubiquitination and proteasomal degradation, thereby enhancing the histone H4 acetylation–dependent transcription of autophagy-related genes. Conclusion: Our findings identify TRIM68 as a key epigenetic regulator of autophagy in sepsis-induced liver injury, mediating TIP60-dependent histone H4 acetylation to drive autophagy gene transcription, and support the therapeutic potential of targeting the TRIM68–TIP60 axis.