BACH2 alleviates immune checkpoint inhibitors‐induced cardiac pyroptosis via transcriptionally promoting GRSF1

Background Immunotherapy has revolutionized the treatment of malignant tumors; however, it may lead to fatal cardiotoxicity. Herein, we explored the mechanisms underlying cardiac side‐effects induced by immune checkpoint inhibitors (ICIs) and proposed a promising therapeutic target. Methods Serum samples were collected from 168 patients with advanced non‐small cell lung cancer (NSCLC) receiving ICIs treatment or not. Representative ICI (IBI308) was intraperitoneally injected into normal C57BL/6 and congenital immune deficient nude mice. NOD‐like receptor family, pyrin domain containing 3 ( Nlrp3 ) globally knockout mice and gasdermin D ( Gsdmd ) globally knockout mice were involved in this study. Mice with cardiac‐specific BTB domain and CNC homolog 2 (Bach2) knock‐in and knock‐out were also included. The Cleavage Under Targets and Tagmentation (CUT&Tag) experiment was conducted to identify downstream molecules of BACH2, which was further validated with dual‐luciferase and electrophoretic mobility shift assays (EMSA). A library of small‐molecule products was screened to identify a specific agonist of BACH2, followed by in vivo and in vitro verification. Results Patients treated with ICIs had significantly higher cardiac troponin T (cTNT) and interleukin 18 (IL‐18) levels. IBI308 significantly reduced cardiac function, increased cardiac fibrosis, and induced myocyte pyroptosis in wild type mice and T‐cell deficient nude mice. IBI308‐elicited toxicity was reversed by depleting pyroptotic genes Nlrp3 or Gsdmd . Furthermore, cardiac‐specific knock‐in of Bach2 rescued, whereas cardiac‐specific knock‐out of Bach2 exacerbated IBI308‐induced cardiotoxicity and pyroptosis. BACH2 directly bound to the promoter of G‐Rich RNA sequence binding factor 1 ( GRSF1 ) and promoted its transcription, which then activated the nuclear factor κB (NF‐κB) signaling cascade. The protective effect of BACH2 was dismissed after knockdown of GRSF1 or inhibition of the NF‐κB pathway. Lipoic acid was identified as an activator of BACH2 and reversed IBI308‐induced pyroptosis in a BACH2‐dependent manner. Conclusions ICIs treatments caused preclinical cardiac injuries by activating myocyte pyroptosis. BACH2 exerted protective effects by promoting GRSF1 transcription and suppressing pyroptosis. Lipoic acid attenuated ICI‐induced cardiotoxicity by upregulating BACH2, which might be a novel therapeutic strategy. Key points Immune checkpoint inhibitors cause elevated cardiac injuries in humans and mice ICIs cause myocyte pyroptosis and cardiotoxicity not via the adaptive immune system BACH2 ameliorates ICIs‐induced pyroptosis through transcriptionally promoting GRSF1 . Lipoic acid as a transcriptional inducer of BACH2 suppresses ICIs‐induced cardiotoxicity