Abstract
Ferroptosis, an iron‑catalyzed form of regulated cell death driven by lipid peroxidation‑induced membrane rupture, has emerged as a critical determinant of cellular fate across diverse physiological and pathological contexts. Simultaneously, lactate has undergone a notable conceptual transformation, evolving from being regarded as merely a glycolytic waste product to being recognized as a key signaling metabolite that modulates iron homeostasis, lipid dynamics, cellular redox balance and the immune response. This metabolic renaissance has revealed an intricate lactate‑ferroptosis regulatory network with implications for human disease. Notably, lactate exhibits diametrically contrasting effects on ferroptosis susceptibility: Promoting cell death in certain contexts while conferring protection in others. This apparent paradox, particularly evident when contrasting tumor and normal cell responses, suggests sophisticated context‑dependent regulatory mechanisms that are yet to be fully elucidated. The present review explores the molecular basis of both ferroptosis execution and lactate signaling, synthesizing recent advances that illuminate their dynamic interplay. Crucially, the present review discusses putative key contextual determinants, including the metabolic state, pH tolerance and antioxidant capacity, which may govern divergent roles of lactate in ferroptosis regulation. Furthermore, understanding these context‑specific mechanisms promises to unlock new therapeutic strategies for diseases ranging from cancer to neurodegeneration, where the lactate‑ferroptosis axis represents both a vulnerability and an opportunity.