Long non-coding RNA TTN-AS1 promotes acute liver injury in sepsis: A novel potential monitoring and therapeutic target

Sepsis-associated liver injury (SALI) is a severe complication of sepsis that markedly worsens clinical outcomes. Currently, specific early diagnostic biomarkers and effective therapeutic strategies remain limited. In this study, we integrated whole-blood transcriptomic sequencing data from patients with SALI with gene expression data obtained from the publicly available dataset to identify key regulatory factors involved in disease pathogenesis. By combining weighted gene co-expression network analysis (WGCNA), differential expression analysis, and construction of a competing endogenous RNA (ceRNA) network, we identified the long non-coding RNA (lncRNA) TTN-AS1 as a potential regulatory molecule. The upregulation of TTN-AS1 in SALI was further validated using an independent public dataset. Functional validation was performed using a cecal ligation and puncture (CLP) mouse model. Overexpression of TTN-AS1 markedly aggravated liver injury, as demonstrated by significantly increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (P < 0.001), elevated concentrations of the inflammatory cytokines, disrupted hepatic architecture and enhanced inflammatory cell infiltration, increased expression of the apoptosis-related proteins Caspase-3 (P < 0.001) and BCL2-associated X (BAX) (P < 0.01), and a higher number of apoptotic hepatocyte as determined (P < 0.001). Mechanistically, the results suggest that TTN-AS1 may contribute to SALI by modulating inflammatory signaling through a microRNA-mediated post-transcriptional regulatory network. In summary, this study provides evidence that lncRNA TTN-AS1 promotes the progression of SALI, highlighting its potential value as a diagnostic biomarker and a therapeutic target. Nevertheless, the tissue-specific expression patterns of TTN-AS1 and the mechanisms underlying its functional heterogeneity require further investigation.