Apoptosis regulates intestinal regeneration via iPLA2 and EGFL7 signaling in Apostichopus japonicus

Apoptosis preserves organismal homeostasis by selectively eliminating unnecessary or damaged cells, with accumulating evidence also suggesting that it activates regenerative pathways and facilitates tissue remodeling. To date, however, the regulatory mechanisms linking this form of programmed cell death to regeneration remain poorly defined, particularly in evolutionarily basal organisms. Using the sea cucumber (Apostichopus japonicus) as a model for intestinal regeneration, this study identified robust apoptotic activity across key regenerative stages. Pharmacological suppression of apoptosis during wound healing and mesenteric scaffold formation critically impaired intestinal regeneration. Quantitative proteomics using direct data-independent acquisition (DIA) revealed coordinated down-regulation of lipid metabolic pathways under apoptosis-inhibited conditions, with notable suppression of Ca²⁺-independent phospholipase A2 (iPLA2), an enzyme typically up-regulated during successful regeneration. In parallel, expression of regeneration-associated factors WNT6 and EGFL7 was markedly reduced under apoptotic blockade. Targeted inhibition of iPLA2, EGFL7, or WNT6 each resulted in impaired mesenteric outgrowth and reduced proliferative activity within the regenerating intestinal primordia. Collectively, these findings suggest two potential mechanistic pathways: apoptosis-mediated regeneration of lipid metabolism via iPLA2 and apoptosis-dependent activation of WNT6/EGFL7 signaling. This study provides mechanistic insight into apoptosis-coupled regenerative processes in basal deuterostomes and expands the conceptual framework of programmed cell death in tissue renewal.