An LCK/PPARG/SCD Lipid Metabolism Axis Promotes Invasion in Human Oral Cancer

ABSTRACT Oral squamous cell carcinoma (OSCC) frequently metastasizes to regional lymph nodes, yet the metabolic adaptations that enable invasive dissemination remain incompletely understood. Although lipid metabolic reprogramming has emerged as a hallmark of metastatic dissemination, the upstream signaling pathways coordinating these processes remain poorly defined. Here, we combined transcriptomic, epigenomic, and lipidomic analyses with genetic and pharmacological perturbation of lymphocyte cell‐specific protein tyrosine kinase (LCK) and peroxisome proliferator‐activated receptor gamma (PPARG) to define the signaling network linking oncogenic kinase activity to lipid metabolism. We identify PPARG as a critical downstream effector of LCK that promotes invasion by reprogramming lipid metabolism. Mechanistically, LCK maintained PPARG expression, which induced stearoyl‐CoA desaturase (SCD), increased monounsaturated fatty acid synthesis, and limited lipid peroxide accumulation. Pharmacological inhibition of SCD suppressed cancer cell invasion, impaired viability, and sensitized PPARG‐activated cells to ferroptosis‐associated cell death. Together, these findings establish an LCK/PPARG/SCD signaling axis that couples oncogenic signaling to lipid metabolic plasticity during OSCC invasion. Our study identifies SCD as a potential therapeutic vulnerability and suggests that therapeutic activation of PPARG signaling should be approached with caution in patients with established oral cancer and carefully evaluated in biomarker‐guided clinical studies.