Defensins and Regulated Cell Death Effectors: Convergent Mechanisms of Membrane Targeting in Innate Immunity

ABSTRACT Targeted disruption of biological membranes represents one of the most effective and evolutionarily conserved mechanisms by which innate immune systems eliminate microbial pathogens and damaged host cells. Membrane susceptibility is determined by lipid composition, with selective recognition of membrane lipids directing membrane targeting by innate immune effectors. Defensins, gasdermins (GSDMs), and mixed lineage kinase domain‐like protein (MLKL) exploit distinct lipid environments to achieve selective membrane targeting despite their diverse biological functions. Defensins, the largest family of host defense peptides, mediate antimicrobial activity predominantly through lipid‐directed membrane disruption, whereas GSDMs and MLKL execute pyroptotic and necroptotic cell death, respectively, through regulated membrane permeabilization. Although these protein families have largely been studied in separate biological contexts, recent structural and mechanistic studies reveal striking convergence in the molecular processes that underpin membrane disruption. Despite assembling into structurally distinct oligomeric architectures such as fibrils, carpet‐like assemblies, and transmembrane pores, these effectors converge on a common order of lipid recognition, supramolecular assembly, and membrane permeabilization. Here, we examine how lipid recognition directs membrane targeting, oligomerization, supramolecular assembly, and membrane permeabilization across these diverse innate immune effectors. We further highlight the expanding functional repertoire of defensins beyond antimicrobial activity, including their ability to selectively target dysregulated tumor membranes through lipid‐dependent membrane recognition and supramolecular assembly. Together, these shared mechanisms establish lipid recognition as a unifying principle of innate immune membrane disruption and support the notion that defensins, GSDMs and MLKL, collectively define a broader family of lipid‐directed innate immune execution systems.