Clinical and translational medicine · 2026
BACH2 alleviates immune checkpoint inhibitors-induced cardiac pyroptosis via transcriptionally promoting GRSF1.
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Cao Mengying, Liu Zilong, Zhao Di, Zhang Hongyuan, He Xinjie, Wang Wenhao, Wang Xiaolin, Yang Cheng, Gao Pan, Zou Yunzeng
Аннотация
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.
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.