Keloids as a Spectrum of Auto-Inflammatory Fibrotic Disorders: Beyond the Conventional Wound-Healing Paradigm

Abstract

Keloids have traditionally been classified as fibroproliferative disorders; however, emerging evidence establishes chronic inflammation and immune dysregulation as the central pathogenic nexus, orchestrating a self-sustaining cycle of pathological healing. This review proposes a paradigm shift toward understanding keloids as a spectrum of auto-inflammatory fibrotic disorders. We synthesize recent advances to demonstrate how genetic predisposition and epigenetic modifications prime a hyperinflammatory response, which is then amplified by endocrine factors and executed through aberrant signaling pathways. Crucially, this inflammatory milieu drives the metabolic reprogramming of fibroblasts toward a Warburg-like phenotype, providing the bioenergetic and biosynthetic substrate for relentless proliferation and extracellular matrix (ECM) deposition. Infiltration and skewed polarization of immune cells further fuel this fibro-inflammatory cascade. Our integrative framework, positioning dysregulated immunity as the disease core, explains keloid persistence, recurrence, and heterogeneity, thereby providing a rationale for combination-based, mechanism-driven therapies. Ultimately, this perspective illuminates novel therapeutic strategies that target the inflammatory core (eg, biologic agents against Th2 cytokines and mast cell products) and its downstream consequences (eg, metabolic inhibitors), offering hope for more effective, mechanism-based interventions against this recalcitrant condition.