The mechanisms by which free heme exacerbates sepsis and the potential therapeutic targets.

Sepsis is marked by high morbidity and mortality rates, representing a significant contributor to the global disease burden. However, due to an incomplete understanding of its pathological mechanisms, current treatments remain predominantly symptomatic and supportive, lacking effective targeted therapies. Recent advances in research have brought the role of free heme in sepsis progression into focus. Free heme is now recognized as a critical mediator of sepsis exacerbation, with its biological properties and pathological mechanisms both playing pivotal roles. This review synthesizes evidence from foundational studies and clinical investigations to elucidate how free heme aggravates sepsis through direct cytotoxic effects and interactions with regulated cell death pathways. Furthermore, based on these mechanisms, potential therapeutic targets are proposed, alongside a summary of promising pharmaceutical candidates currently under investigation.