The regulated cell death nexus: From molecular mechanisms to NINJ1-mediated membrane rupture

Regulated cell death (RCD) is a fundamental, genetically programmed process essential for maintaining intracellular homeostasis and orchestrating physiological functions. Mounting evidence has established that distinct RCD pathways-including apoptosis, pyroptosis, ferroptosis, and necroptosis-play pivotal and complex roles in the pathogenesis of a wide spectrum of diseases, such as cancers, metabolic dysfunctions, neurodegenerative impairments, and inflammatory disorders. However, the intricate molecular interplay between these cell death modalities and their collective impact on disease progression remains to be fully elucidated. This review systematically delineates the molecular underpinnings of major RCD pathways, with a particular emphasis on the sophisticated crosstalk among them. Furthermore, we explore the emerging role of NINJ1, a key executioner of plasma membrane rupture, as a novel regulator unifying the terminal phase of multiple lytic cell death processes. Importantly, we discuss how recent advances in nanomedicine offer promising strategies to overcome the clinical translation challenges of RCD-targeting agents, enabling spatiotemporally controlled modulation of cell death pathways and enhancing therapeutic precision. Finally, we discuss the therapeutic potential of targeting specific RCD pathways and their nodal regulators, as well as the integration of nanomedicine-based approaches, highlighting innovative strategies for mitigating disease burden and advancing future public health initiatives.