ACSS3 protein macromolecule regulates glycolysis in keloid through Wnt/β-catenin signaling pathway: Bioinformatics, machine learning, and experimental validation.

Abstract

Keloids are fibroproliferative lesions resulting from abnormal wound healing, characterized by the excessive growth and metabolic reprogramming of keloid fibroblasts (KFs). The underlying mechanisms responsible for these metabolic abnormalities remain under debate. This research employed comprehensive bioinformatics techniques to pinpoint ACSS3 (Acetyl-CoA Synthetase Short-Chain Family Member 3) and the Wnt/β-Catenin pathway as pivotal contributors to keloid pathogenesis. ACSS3, a mitochondrial protein involved in metabolic regulation, is downregulated in keloid. Lentiviral transfection-induced overexpression of ACSS3 suppressed KFs activity, normalized glycolytic flux, and reduced the levels of critical glycolytic enzymes. Conversely, ACSS3 knockdown elicited opposite effects, which were reversed by ICG-001. Single-cell analysis demonstrates that fibroblasts are the primary cell type involved in the fibrotic process. An ACSS3 regulatory network was developed. Additionally, Molecular docking and dynamics simulations were conducted to identify potential drugs targeting ACSS3. In summary, this study demonstrates that ACSS3 modulates aerobic glycolysis and the activity of KFs via the Wnt/β-Catenin pathway, positioning ACSS3 as a promising therapeutic target for keloid treatment.