Transcriptome sequencing of cavernous fibroblasts cultured on substrates with different stiffness.

Fibrotic diseases involve increased mechanical stress due to extracellular matrix deposition, significantly altering cellular metabolism. However, a systematic understanding of how mechanical force regulates lipid metabolism across different molecular layers remains limited. We employed an integrated multi-omics approach, including transcriptomics, Ribo-seq, proteomics, and lipidomics, to comprehensively assess the effects of mechanical stretch on lipid metabolism in human cavernous fibroblasts. Our analysis revealed that while mechanical force elicits complex multi-layered responses, post-translational regulation predominantly drives this lipid metabolic reprogramming. Lipidomics identified a significant reduction in fatty acids and an upregulation of ganglioside. Key genes central to this mechanosensitive metabolic shift were pinpointed. This study demonstrates that mechanical force hierarchically reprograms lipid metabolism. The shift from fatty acids to ganglioside underscores a key metabolic adaptation in fibroblasts. Targeting the identified critical genes may offer a promising therapeutic strategy for fibrosis-related diseases.