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Herein, we explored the mechanisms underlying cardiac side\u2010effects induced by immune checkpoint inhibitors (ICIs) and proposed a promising therapeutic target.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Serum samples were collected from 168 patients with advanced non\u2010small 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\u2010like receptor family, pyrin domain containing 3 (\n                      <jats:italic>Nlrp3<\/jats:italic>\n                      ) globally knockout mice and gasdermin D (\n                      <jats:italic>Gsdmd<\/jats:italic>\n                      ) globally knockout mice were involved in this study. Mice with cardiac\u2010specific BTB domain and CNC homolog 2 (Bach2) knock\u2010in and knock\u2010out were also included. The Cleavage Under Targets and Tagmentation (CUT&amp;Tag) experiment was conducted to identify downstream molecules of BACH2, which was further validated with dual\u2010luciferase and electrophoretic mobility shift assays (EMSA). A library of small\u2010molecule products was screened to identify a specific agonist of BACH2, followed by in vivo and in vitro verification.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Patients treated with ICIs had significantly higher cardiac troponin T (cTNT) and interleukin 18 (IL\u201018) levels. IBI308 significantly reduced cardiac function, increased cardiac fibrosis, and induced myocyte pyroptosis in wild type mice and T\u2010cell deficient nude mice. IBI308\u2010elicited toxicity was reversed by depleting pyroptotic genes\n                      <jats:italic>Nlrp3<\/jats:italic>\n                      or\n                      <jats:italic>Gsdmd<\/jats:italic>\n                      . Furthermore, cardiac\u2010specific knock\u2010in of Bach2 rescued, whereas cardiac\u2010specific knock\u2010out of Bach2 exacerbated IBI308\u2010induced cardiotoxicity and pyroptosis. BACH2 directly bound to the promoter of G\u2010Rich RNA sequence binding factor 1 (\n                      <jats:italic>GRSF1<\/jats:italic>\n                      ) and promoted its transcription, which then activated the nuclear factor \u03baB (NF\u2010\u03baB) signaling cascade. The protective effect of BACH2 was dismissed after knockdown of\n                      <jats:italic>GRSF1<\/jats:italic>\n                      or inhibition of the NF\u2010\u03baB pathway. Lipoic acid was identified as an activator of BACH2 and reversed IBI308\u2010induced pyroptosis in a BACH2\u2010dependent manner.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      ICIs treatments caused preclinical cardiac injuries by activating myocyte pyroptosis. BACH2 exerted protective effects by promoting\n                      <jats:italic>GRSF1<\/jats:italic>\n                      transcription and suppressing pyroptosis. Lipoic acid attenuated ICI\u2010induced cardiotoxicity by upregulating BACH2, which might be a novel therapeutic strategy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Immune checkpoint inhibitors cause elevated cardiac injuries in humans and mice<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>ICIs cause myocyte pyroptosis and cardiotoxicity not via the adaptive immune system<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            BACH2 ameliorates ICIs\u2010induced pyroptosis through transcriptionally promoting\n                            <jats:italic>GRSF1<\/jats:italic>\n                            .\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Lipoic acid as a transcriptional inducer of BACH2 suppresses ICIs\u2010induced cardiotoxicity<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70618","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T17:04:51Z","timestamp":1770743091000},"source":"Crossref","is-referenced-by-count":2,"title":["BACH2 alleviates immune checkpoint inhibitors\u2010induced cardiac pyroptosis via transcriptionally promoting GRSF1"],"prefix":"10.1002","volume":"16","author":[{"given":"Mengying","family":"Cao","sequence":"first","affiliation":[{"name":"Shanghai Institute of Cardiovascular Diseases and State Key Laboratory 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