Histone chaperone HIRA restrains ferroptosis susceptibility through epigenetic control of iron metabolism in prostate cancer.

Ferroptosis, an iron-dependent form of immunogenic cell death (ICD), represents a promising anti-tumor therapeutic strategy via effectively activating immune responses. However, the regulatory mechanisms governing ferroptosis in prostate cancer remain poorly understood, significantly impeding the development of targeted therapeutic approaches. Through genome-wide CRISPR/Cas9 screening, we identified the histone chaperone HIRA as a novel ferroptosis suppressor in prostate cancer. Integrated analysis of public datasets and immunohistochemical validation demonstrated significant HIRA overexpression in prostate tumors, which was associated with diminished cytotoxic T lymphocyte infiltration and adverse clinical outcomes. Moreover, depletion of HIRA substantially enhanced ferroptosis susceptibility in vitro and in vivo, resulting in marked tumor growth inhibition. Mechanistic investigations revealed that HIRA orchestrates iron homeostasis through coordinated epigenetic regulation. While traditionally known to mediate H3.3 deposition in actively transcribed regions, we unexpectedly observed that HIRA depletion induced a widespread redistribution of H3.3 occupancy, with more regions gained than lost, suggesting compensatory H3.3 deposition dynamics. This redistribution coincided with increased chromatin accessibility and transcriptional regulation of iron metabolism genes, ultimately attenuating intracellular Fe2+ accumulation and ferroptosis resistance. Notably, HIRA depletion augmented CD4+ and CD8+ T cell infiltration and demonstrated synergistic efficacy with PD-1 immune checkpoint blockade in PCa models. Thus, our study establishes HIRA as an important epigenetic regulator of ferroptosis through iron metabolism modulation and nominates it as a promising therapeutic target for combination therapy in advanced prostate cancer.