Evolving role of mitochondrial dysfunction and mitophagy in necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is a severe, multifactorial disease of prematurity characterized by a heterogeneous pathophysiology. A dysregulated cytokine-driven inflammatory response is central to its progression, underscoring the need to identify key molecular triggers and pathways. Emerging evidence suggests that mitochondrial dysfunction represents a central nidus linking microbial signals to immune responses, and ultimately to epithelial injury. Future studies defining the timing and mechanisms of mitochondrial dysfunction and the role of mitophagy to better understand the interplay of the microbiome, immune responses, and mitochondria in the pathogenesis of NEC are greatly needed. IMPACT: Mitochondrial dysfunction is central to NEC pathogenesis, linking dysbiosis, immune dysregulation, and epithelial injury, and redefining NEC as an immunometabolic disease. ACSL1 emerges as a promising biomarker and therapeutic target, with potential to guide early diagnosis and modulate inflammation and oxidative stress. Future focus on timing and mitophagy may enable early detection and targeted interventions before irreversible intestinal injury develops, improving outcomes in NEC.