Linoleic acid drives human hypertrophic scar derived fibroblasts toward a PLIN2 + /PPARγ + lipo-fibroblast phenotype.

Activated myofibroblasts are considered the primary drivers of hypertrophic scar (HS) formation. Although traditionally viewed as terminally differentiated, recent evidence in pulmonary fibrosis suggests that myofibroblasts can be transformed toward lipo-fibroblasts, representing a potential pathway for fibrosis resolution. Whether a similar phenotypic transition occurs in skin scarring remains unexplored. Given the role of linoleic acid (LA) in adipogenesis, this study aimed to investigate whether LA can induce the transition of hypertrophic scar derived fibroblasts (HS-fibroblasts) into lipo-fibroblast phenotype and contribute to the fibrosis resolution. HS-fibroblasts were treated with 100-200 μM LA and analyzed by Oil red O staining for lipid droplet formation. Expression of fibrosis-related markers (COL1A1, COL3A1, CDC42 and α-SMA) and lipid metabolism regulators (PPARα, PPARγ and Perilipin-2) were assessed via Western blot and RT-qPCR. Lateral cell migration was evaluated using a scratch wound assay, and viability was measured by CCK-8 assay. LA drives the transition of HS-fibroblasts into lipo-fibroblasts phenotype in vitro. It is defined by Oil red O-confirmed lipid droplet accumulation together with reduced fibrotic marker expression (COL1A1(P＜0.05), α-SMA (P＜0.05), CDC42 (P＜0.01)) and increased adipogenic regulator expression (PPARγ (P＜0.01), Perilipin-2 (P＜0.05)) after 72 h treatment. LA-induced lipo-fibroblasts phenotype also exhibited reduced lateral migration capacity. However, intracellular triglyceride (TG) synthesis does not seem to be the main driver of the changes induced by LA. LA could drive HS-fibroblasts toward a less fibrotic, lipid-accumulating lipo-fibroblast phenotype in vitro.