Metabolic Checkpoints in Cutaneous Squamous Cell Carcinoma: ACSL1 and PPARD Orchestrate Lipid-Ferroptosis Crosstalk...

Ferroptosis and lipid metabolism disturbances are increasingly recognized as critical factors in cancer biology, yet their specific mechanisms in cutaneous squamous cell carcinoma (CSCC) remain unclear. In this study, we integrated bioinformatics analyses and single-cell RNA sequencing analyses to identify ferroptosis- and lipid-related biomarkers in CSCC. ACSL1, PPARD, and PPARG emerged as key genes enriched in pathways such as cell cycle regulation and Toll-like receptor signaling. Immune infiltration analyses revealed a strong positive correlation between PPARD and CD56^dim natural killer cells, and a negative correlation between PPARG and activated dendritic cells. Single-cell transcriptomic profiling pinpointed keratinocytes as central players, with ACSL1 and PPARD exhibiting dynamic expression patterns during differentiation. RT-qPCR validation in clinical CSCC tissues confirmed elevated PPARD expression and reduced ACSL1 expression. These findings suggest an association between ACSL1/PPARD and the lipid-ferroptosis interplay via keratinocyte remodeling, rather than establishing causality. Accordingly, we frame ACSL1 and PPARD as candidate markers pending protein-level and functional validation.