Chronic fibrotic diseases across organs are driven by a conserved, self-perpetuating cycle of injury, inflammation, cell differentiation, and scarring. An insult (e.g., environmental toxins, pathogens, genetic predisposition) begins the cycle. Insult leads to injury via cellular stress that activates the endoplasmic reticulum unfolded protein response (UPR), releases alarmins and mitochondrial reactive oxygen species, and culminates in epithelial cell death. These events initiate the inflammatory phase due to platelet infiltration, recruitment of innate immune cells (e.g., monocytes/macrophages, neutrophils, dendritic cells, DCs), and activation of adaptive immune responses (Th2 cells, Th17 cells, Tregs, B cells), orchestrated primarily by a milieu of type 2 and type 3 cytokines. This immune activation induces the loss of tissue homeostasis and primes the fibrotic niche. During the differentiation phase, endothelial cells undergo defenestration with loss of endothelium integrity and a switch to a pro-inflammatory/recruitment phenotype, while resident macrophages are depleted and replaced by monocyte-derived profibrotic/pathogenic macrophages. Fibroblasts differentiate into myofibroblasts, acquiring contractile and extracellular matrix–producing (ECM-producing) phenotypes aimed first at injury resolution and tissue repair. If resolution and repair are unsuccessful, the scarring phase is perpetuated by excessive ECM deposition, reduced matrix degradation due to MMP/tissue inhibitor of metalloproteinases (TIMP) imbalance, and increased tissue stiffness that contribute to scar blockade. These changes impair epithelial regeneration, restrict perfusion, and reinforce the fibrotic microenvironment, thereby alimenting the cycle. Failure to interrupt this cycle leads to progressive fibrosis and organ dysfunction. The right panel shows currently approved antifibrotic therapies (in bold and larger font: Esbriet [pirfedinone] for IPF, Ofev [nintedanib] and Jascayd [nerandomilast] for IPF/progressive pulmonary fibrosis, Actemra [tocilizumab] for systemic sclerosis–ILD, Rezdiffra [resmetirom] and Wegovy [semaglutide] for MASH; in strikethrough: active or stopped phase II/III assets and their relative impact on the “core” fibrotic mechanisms of injury, inflammation, differentiation, and scarring).