The hsa_circ_0082152 maintains NF-κB mRNA stability by binding to MTDH to promote anti-tuberculosis drug-induced liver injury

Abstract

Anti-tuberculosis drug-induced liver injury (ADLI) is a common adverse reaction during anti-tuberculosis treatment and often leads to treatment interruptions. Circular RNAs (circRNAs) have been identified as key modulators in liver diseases. CircRNAs is a special class of noncoding RNAs that have been found to have significant impacts on the progression of inflammation via various mechanisms. In the serum of ADLI patients, upregulation of the circular RNA hsa_circ_0082152 (derived from the host gene snd1) was observed, along with increased ALT and AST levels, as well as alterations in the levels of inflammation-related factors such as NF-κB, IL-1β and TNF-α. To elucidate the underlying mechanisms, we established an HL-7702-ADLI cell model and confirmed similar upregulation of hsa_circ_0082152. Downregulation of hsa_circ_0082152 significantly inhibited inflammatory injury in ADLI cells, while upregulation had the opposite effect. RNA immunoprecipitation showed that hsa_circ_0082152 functions by interacting with metadherin (MTDH). Our study further verified that the interaction of hsa_circ_0082152 with the MTDH protein binding to NF-κB mRNA to maintain NF-κB mRNA stability, which increases the expression of NF-κB and its targets IL-1β and TNF-α. Conversely, depletion of MTDH rescued the promotive effect of hsa_circ_0082152 overexpression on ADLI inflammation. Therefore, hsa_circ_0082152 overexpression promotes ADLI progression via the MTDH/NF-κB axis.

Keywords: Anti-tuberculosis drug-induced liver injury; NF-κB; hsa_circ_0082152.