Inhibition of HSPA8 by rifampicin contributes to ferroptosis via enhancing autophagy

Abstract

Background and Aim Rifampicin is the most common pathogenic factor in anti‐tuberculosis drug‐induced liver injury (AT‐DILI), the mechanisms that it promotes hepatocyte damage in AT‐DILI are not yet to be thoroughly elucidated. In this study, we investigated the potential molecular mechanisms for ferroptosis involving rifampicin hepatotoxicity. Methods Animal and cell injury models of rifampicin were constructed, and the toxicity of rifampicin was assessed by physicochemical staining and cell viability assay. Next, flow cytometry was employed to detect changes in ferroptosis‐related markers, and Western blotting was used to detect protein expression. Then, the important role of autophagy and ferroptosis was verified with small molecule compound intervention. Results We found that ferritinophagy‐induced ferroptosis participates in the toxicity of rifampicin, and the mechanism is that rifampicin precisely activates high‐throughput autophagy, which leads to the massive degradation of ferritin and the increase of free iron. Moreover, rifampicin exhibited conspicuous inhibition of Human 71 kDa heat shock cognate protein (HSPA8) that is intimately associated with Microtubule‐associated protein light chain 3 isoform B (LC3B) expression, in turn, HSPA8 inducer attenuated intracellular autophagy flux. Of note, inducing HSPA8 or inhibition of autophagy and ferroptosis considerably relieved the hepatotoxicity of rifampicin in mouse model. Conclusions The present study highlights the crucial roles of the HSPA8 and autophagy in ferroptotic cell death driving by rifampicin, particularly illumines multiple promising regulatory nodes for therapeutic interventions in diseases involving AT‐DILI.

The Emerging Role of Ferroptosis in Various Chronic Liver Diseases: Opportunity or Challenge

“…Cyproterone acetate, an antitumor drug, caused liver cirrhosis with iron overload. 28 Efavirenz, 29 rifampicin, 30 and isoniazid 31 are found to impair ATP biosynthesis by regulating ferritin or ferroptosis-related genes. High doses of auranofin can cause liver lipid peroxidation and ferroptosis by inhibiting the activity of thioredoxin reductase.…”

Intracellular Protein Adsorption Behavior and Biological Effects of Polystyrene Nanoplastics in THP-1 Cells

“…It also functions as a lattice protein in delaminating ATPase in clathrin-mediated endocytosis . HSPA8 is also involved in cellular protein degradation and plays an important role in autophagy …”

“…67 HSPA8 is also involved in cellular protein degradation and plays an important role in autophagy. 68 It indicated the adsorption of HSPA8 onto NPs in THP-1 cells (Figure 6C). HSPA8 plays a role in protein folding and clathrin-mediated endocytosis, as do RPN1 and CLTC, respectively.…”

Ferritinophagy: research advance and clinical significance in cancers

“…Clinically, we need to know not only the drug efficacy, but also the adverse effects and the conditions of application of each drug to avoid additional serious damage to patients body. Rifampicin, the most common causative agent of antituberculosis drug-induced liver injury (AT-DILI), can reduce the hepatotoxicity of rifampicin by activating the autophagic pathway to reduce ferritinophagy and ferroptosis [ 90 ]. Additionally, the anticancer antibiotic Adriamycin was observed to enhance ferritinophagy by affecting the SPATA2/CYLD pathway, leading to NCOA4 depletion and ferroptosis induction in cardiomyocytes [ 91 ].…”