Targeting cardiomyocyte GBP5 mitigates cardiac inflammatory injury

Abstract

Cardiac inflammation is a serious adverse effect of contemporary cancer therapies, including immune checkpoint inhibitors (ICIs), anthracyclines, and thoracic irradiation. Although distinct molecular mechanisms contribute to therapy-related cardiotoxicity, shared signaling nodes remain insufficiently characterized. We recently identified guanylate-binding protein 5 (GBP5), a key regulator of NLRP3 inflammasome assembly, as a potential mediator of treatment-induced myocardial inflammation. To define the cardiomyocyte-specific function of GBP5, we generated an inducible, cardiomyocyte-specific knock-in mouse model expressing a truncated, dysfunctional GBP5 variant (GBP5-cKI) lacking the C-terminal domain required for membrane localization and inflammasome assembly. GBP5-cKI and wild-type (WT) mice were subjected to: (i) combined anti–PD-1/anti–CTLA-4 therapy ± IFNγ to model ICI-associated myocarditis; or (ii) doxorubicin administration (3 mg/kg i.p. every 2 days for 8 doses) to induce anthracycline cardiotoxicity; or (iii) 16 Gy thoracic photon irradiation to study radiation-induced cardiac injury. Cardiac function, inflammatory responses, and structural remodeling were assessed by echocardiography, histological analysis, and quantitative PCR. GBP5 expression was markedly increased in all preclinical models of therapy-induced cardiac injury. In contrast to WT controls, cardiomyocyte-specific inactivation of GBP5 significantly attenuated myocardial inflammation, cardiac inflammasome activation (Caspase-1, IL-1β), and pathological remodeling across all oncological treatments. Importantly, GBP5-cKI mice exhibited preserved left ventricular function and improved survival compared with WT controls.

These findings identify cardiomyocyte GBP5 as a central regulator of inflammasome-driven myocardial injury in response to cancer therapies. Targeted inactivation of cardiac GBP5 may therefore represent a novel therapeutic strategy to prevent immune-, chemotherapy-, and radiation-induced cardiotoxicity.