Ferroptosis-immune crosstalk in ionizing radiation-induced testicular injury: mechanisms and therapeutic opportunities.

Accumulating evidence suggests that ferroptosis-an iron-dependent, lipid peroxidation-driven form of regulated cell death-may contribute substantially to ionizing radiation (IR)-induced testicular injury. In this review, we develop a hypothesis-generating framework for ferroptosis-immune crosstalk in the testis. Within this framework, ferroptotic injury to Sertoli cells is proposed to compromise the blood-testis barrier (BTB), potentially facilitating autoantigen exposure and adaptive immune activation; reciprocal inflammatory signaling may, in turn, increase the susceptibility of neighboring cells to ferroptosis. Potential interactions between ferroptosis and apoptosis, autophagy, pyroptosis, and necroptosis are considered as additional components of this proposed network. We summarize clinically used drugs and emerging strategies targeting ferroptosis, including iron chelators, radical scavengers, NRF2 activators, natural antioxidants, and nanomedicine. Key challenges such as the temporal dynamics of ferroptosis, dose-dependent effects, and translational gaps are discussed. This framework is intended to organize current evidence, identify testable mechanistic links, and guide future studies of male fertility preservation through ferroptosis-immune modulation.