TNFAIP8 Deficiency Attenuates Doxorubicin-Induced Cardiotoxicity by Inhibiting Oxidative Stress and Inflammation Via TLR4/NF-κB Signaling.

Doxorubicin-induced cardiotoxicity (DIC) is pathologically characterized by oxidative stress and inflammatory cascades, creating an urgent need to identify therapeutic targets modulating these processes. While tumor necrosis factor alpha-induced protein 8 (TNFAIP8) has emerged as a regulator of inflammation and apoptosis, its functional role in DIC remains unexplored. This study systematically investigates TNFAIP8's cardioprotective mechanisms against DIC. A chronic DIC model was established in male C57BL/6 mice through intraperitoneal doxorubicin (DOX) administration (4 mg/kg weekly for 4 weeks; cumulative dose 16 mg/kg). TNFAIP8 knockdown was achieved via AAV9-delivered shRNA through tail vein injection. Multimodal assessment integrating echocardiography, histopathology analysis, and molecular profiling elucidated TNFAIP8's functional and mechanistic contributions. In DOX-induced cardiomyocytes, TNFAIP8 expression was upregulated. The absence of TNFAIP8 markedly reduced DOX-triggered oxidative stress and inflammatory responses. The potential protective mechanism of TNFAIP8 deficiency against DIC involves toll-like receptor 4 (TLR4)/NF-κB signaling pathway. Importantly, administration of the TLR4 activator lipopolysaccharide (LPS) substantially reversed the cardioprotective effects observed with TNFAIP8 deletion. Our findings establish TNFAIP8 as a critical regulator of DIC pathophysiology through TLR4/NF-κB axis modulation. Pharmacological TNFAIP8 inhibition represents a viable therapeutic strategy for mitigating chemotherapy-induced cardiac dysfunction. Future investigations should prioritize developing cardiac-targeted TNFAIP8 inhibitors and validating their efficacy in large-animal DIC models.