: Doxorubicin (DOX) is a widely employed chemotherapeutic drug, while its clinical use is limited by the lethal cardiotoxicity. Previous studies highlighted the critical role of cardiomyocyte ferroptosis in the pathogenesis of DOX-induced cardiotoxicity (DIC). Androgen-induced gene 1 (AIG1) is perceived as a key regulator of oxidative stress-mediated cell death. Nonetheless, it remains elusive whether AIG1 is involved in the progression of DOX-induced cardiomyocyte ferroptosis and cardiotoxicity. : C57BL/6 male mice were repeatedly administrated with DOX at an accumulative dosage of 20 mg/kg to establish a chronic DIC model. Global AIG1 knockout mice and AAV9-mediated cardiac-specific AIG1 knockdown or overexpression mice were utilized to evaluate the precise role of AIG1 in DIC. Additionally, the effects of AIG1 on cardiomyocyte ferroptosis were further investigated following DOX stimulation. : Ferroptosis played a pivotal role in DIC in both and settings. DOX exposure significantly reduced AIG1 expression levels in cardiomyocytes. Global AIG1 knockout or cardiac-specific AIG1 knockdown mice exhibited deteriorated cardiac function, adverse cardiac remodeling following DOX insult. Moreover, AIG1 deficiency aggravated DOX-evoked ferroptosis and oxidative stress in cardiomyocytes, whereas cardiac-specific overexpression of AIG1 conferred the protective effects manifested by the inhibition of cardiomyocyte ferroptosis and improvements in cardiac performance and remodeling under DOX challenge. Mechanistically, AIG1 directly interacted with the Pirh2 E3 ubiquitin ligase to promote the ubiquitination of p53, a key protein governing ferroptosis during DIC, thereby accelerating its degradation. Cardiac-specific Pirh2 knockdown markedly exacerbated DOX-induced ferroptosis by enhancing p53 activity in cardiomyocytes. Furthermore, the pharmacological administration of a highly selective p53 inhibitor PFT-α effectively ameliorated DIC in mice by inhibiting cardiomyocyte ferroptosis and substantially abrogated the deleterious cardiac effects associated with AIG knockout under DOX challenge. : Our findings defined the critical cardioprotective role of AIG1 in DIC by alleviating cardiomyocyte ferroptosis in a Pirh2/p53 axis-dependent manner. Targeting the novelly identified AIG1-Pirh2-p53 signaling axis presents a promising approach to prevent DIC.