Necrosis by Sodium Overload: Mechanisms, Pathophysiological Roles, and Therapeutic Prospects of a Novel Form of...

Sodium ion (Na⁺), the predominant cation in the extracellular space, is essential for maintaining fundamental cellular activities via preservation of the transmembrane Na⁺ gradient. While intracellular Ca²⁺ overload has long been recognized as the core driver of cell injury and death, accumulating evidence indicates that Na⁺ overload, defined as abnormal intracellular Na⁺ accumulation, may act as an independent trigger of irreversible cellular damage, rather than merely a preceding event or concomitant phenomenon of Ca²⁺ overload. In 2025, the term Necrosis by Na⁺ Overload (NECSO) was first coined to describe a novel form of regulated necrosis directly triggered by sustained and excessive Na⁺ influx, which is primarily mediated by the transient receptor potential melastatin 4 (TRPM4) channel. Distinct from apoptosis and other established forms of regulated cell death, NECSO is characterized by early cellular and organellar swelling, mitochondrial energy metabolism collapse, ionic homeostasis disruption, and eventual loss of plasma membrane integrity, without the hallmark features of caspase activation and chromatin condensation. The core execution pathway of NECSO involves TRPM4-mediated Na⁺ influx, subsequent mitochondrial Na⁺ accumulation, impaired tricarboxylic acid cycle and oxidative phosphorylation, and catastrophic cellular energy depletion, which further aggravates Na⁺ overload via inhibition of Na⁺/K⁺-ATPase and forms a fatal vicious cycle. In pathophysiological contexts, NECSO serves as a central mediator of myocardial injury in ischemia-reperfusion, and is also implicated in the progression of heart failure and neuronal death in stroke. In cancer biology, NECSO and its core mediator TRPM4 exhibit highly tissue-specific dual roles, acting as either oncogenic drivers or tumor suppressors in different cancer types. Meanwhile, NECSO-related genes have shown promising potential as diagnostic and prognostic biomarkers, as well as predictors of therapeutic response to chemotherapy and immunotherapy across multiple malignancies. Targeted strategies against NECSO, including direct modulation of TRPM4 activity, intervention of Na⁺ homeostasis, and combination therapeutic regimens, have exhibited favorable efficacy in preclinical models of cardiovascular diseases and cancer. This review systematically summarizes the definition, core molecular mechanisms, and pathophysiological functions of NECSO, discusses the application value of NECSO-related biomarkers, and outlines current challenges and future directions in this emerging field, to provide a novel perspective for the development of therapeutic strategies against major human diseases.