3,3′,5-triiodo-l-thyronine inhibits drug-induced liver injury through activation of PPARα as revealed by network pharmacology and biological experimental verification

Drug-induced liver injury (DILI) has increased in recent years, leading to acute liver failure. 3,3',5-triiodo-l-thyronine (T3) has been reported to exert a potent hepatoprotective effect. However, the mechanism and efficacy of T3 on DILI remain undocumented. In this study, an MTT assay was used to detect the effect of T3 on hepatotoxicity of acetaminophen (APAP) in L02 cells. Then, we screened key targets and related biological pathways by network pharmacology. Finally, enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were used to verify the mechanism and key targets of T3 on DILI. The results of the MTT assay showed that T3 significantly decreased hepatocellular injury induced by APAP. Network pharmacology and bioinformatics analysis showed that 118 intersection targets of T3 and DILI were identified and the mechanism of T3 on DILI was related to cell proliferation and oxidative stress. ELISA results showed that T3 may be an effective treatment for DILI as biomarkers of hepatocellular injury such as AST, ALP were decreased compared to APAP only treated cells, and the mechanism of T3 may be mediated in part through improving redox balance. The topological parameter screening results suggested 12 key targets of T3 for DILI. Among them, PPARα is associated with DILI, and activation of PPARα can reduce oxidative stress and cell necrosis. Therefore, PPARα was identified as a target for verification. qRT-PCR analysis demonstrated that T3 could reverse the down-regulation of PPARα induced by APAP exposure. Taken together, we demonstrated for the first time that T3 could activate PPARα, promote cell proliferation and reduce oxidative stress, and play a vital role in the treatment of DILI, which provides a reference for T3 as a candidate treatment for DILI.