Fueling fibrosis: metabolic dysregulation in systemic sclerosis.

Purpose of review: This review examines how metabolic reprogramming drives fibrosis and immune dysregulation in systemic sclerosis (SSc), emphasizing the role of nutrient-sensing and energy pathways in disease progression.

Recent findings: SSc is characterized by a shift from catabolic to anabolic metabolism, defined by reduced AMP-activated protein kinase (AMPK) and enhanced mechanistic target of rapamycin complex 1 (mTORC1) signaling. This promotes biosynthetic activity, with upregulated glycolysis supplying substrates for collagen production and supporting pro-inflammatory immune cell polarization. Remodeling of the tricarboxylic acid cycle yields key metabolites with extrametabolic roles. α-ketoglutarate (αKG) supports epigenetic regulation, collagen maturation, and AMPK activation, offering protective effects. In contrast, succinate and fumarate promote inflammation and fibrotic signaling. Despite increased anabolic activity, oxidative phosphorylation remains elevated in SSc fibroblasts, contributing to excess reactive oxygen species (ROS). Metabolomic analyses consistently show disrupted amino acid and lipid metabolism, including glutamine and tryptophan pathways, linked to immune activation and fibrogenesis. Single-cell transcriptomics reveal diverse fibroblast subtypes with distinct metabolic programs correlating with fibrosis severity.

Summary: SSc is characterized by a metabolic reprogramming that favors anabolic, profibrotic, and proinflammatory states. These interconnected metabolic shifts illustrate how central carbon and nutrient pathways not only sustain energy demands but also actively regulate profibrotic signaling, offering new therapeutic targets for modulating fibrosis.