Role of persistent necroinflammation in chronic tissue remodeling and organ fibrosis

Abstract

Persistent necroinflammation is a continuous feedback loop between the regulated necrotic cell death and the sustained immune system activation. It has been increasingly recognized as a key driver of chronic tissue remodeling and fibrosis. Necrosis, unlike apoptosis, is a lytic and immunogenic form of cell death that releases danger-associated molecular patterns (DAMPs) and alarmins, which activate inflammatory pathways including the NOD-like receptor protein 3 (NLRP3) inflammasome. This sustained inflammatory environment promotes pathological remodeling and impairs tissue regeneration. This review elucidates the mechanistic framework of necroinflammation involving key molecular players such as receptor-interacting protein kinases (RIPK) 1, RIPK3, mixed lineage kinase domain-like protein (MLKL), NLRP3, calcium/calmodulin-dependent protein kinase II (CaMKII), gasdermin (GSDM), glutathione peroxidase-4 (GPX-4), acyl-CoA synthetase long-chain family member 4 (ACSL4), ferroptosis suppressor protein 1 (FSP1), and their role in fibrotic pathologies across kidneys, heart, liver, lungs, and brain. We emphasize how these signaling pathways further augment transforming growth factor-beta (TGF-b) signaling, thereby contributing to tissue fibrosis in chronic disease conditions. We also highlight recent advances in targeting these necroinflammatory mediators, especially inhibitors of these pathways, as promising antifibrotic therapeutic strategies. We emphasize the urgent need for further research to deepen our understanding of the temporal and spatial dynamics of necroinflammatory signaling and to develop organ-specific, targeted interventions against fibrosis. This will provide a robust foundation for translational research to exploit these pathways in clinical settings to mitigate chronic inflammatory diseases and their fibrotic consequences across multiple organ systems.