HMGB1: a multifaceted mediator of cell death pathways in cardiovascular diseases.

Cardiovascular diseases (CVDs) are a leading cause of death globally, responsible for 32% of all fatalities. They significantly reduce quality of life and life expectancy, while imposing a substantial economic burden on healthcare systems in different countries. High mobility group box 1 (HMGB1), a location-dependent multifunctional protein, plays a significant role in various cell death pathways associated with CVDs. While its release at the early stages of disease may stimulate immune and inflammatory responses, aiding microbial clearance and wound healing, the accumulation of HMGB1 with disease progression disrupts the balance between autophagy and apoptosis. Excessive intracellular and extracellular HMGB1 is implicated in diverse forms of cell death, including PANoptosis, ferroptosis, and efferocytosis, highlighting its complex role in maintaining cellular homeostasis and responding to injury. Understanding the intricate regulatory functions of HMGB1 in these processes is critical for developing targeted therapeutic strategies to address cardiovascular pathologies. Preclinical studies have demonstrated the therapeutic potential of targeting HMGB1 release and expression in various CVD models, establishing it as an attractive therapeutic target. Future research focusing on combined strategies that integrate HMGB1 with other targets holds promise for advancing CVD treatment.