Anti-Lipid Peroxidation Restores Schwann Cell Repair Phenotype and Attenuates PNI-like Behavior in Oral Squamous Cell Carcinoma

Background: Perineural invasion (PNI) is a critical feature of oral squamous cell carcinoma (OSCC), in which Schwann cells are increasingly recognized as active contributors rather than passive structures. However, the mechanisms underlying Schwann cell phenotypic remodeling in the tumor microenvironment remain incompletely understood. This study aimed to investigate whether OSCC-derived signals induce lipid peroxidation and repair-associated phenotypic remodeling in Schwann cells that promote PNI-like tumor cell behavior, and whether inhibiting lipid peroxidation can attenuate these effects.

Methods: An OSCC-conditioned microenvironment was established to investigate whether tumor-derived signals induce lipid peroxidation and phenotypic changes in human Schwann cells (hSCs). Redox status was assessed by LDH, MDA, GSH, and C11-BODIPY assays. Repair-associated markers (c-Jun and NGFR) were evaluated by Western blot, and RSL3 was used as a positive inducer of lipid peroxidation. Schwann cell-conditioned medium (SCM) was applied to assess its effects on OSCC cell migration and invasion. Ferrostatin-1 (Fer-1) was used to inhibit lipid peroxidation.

Results: OSCC-conditioned medium induced significant lipid peroxidation and redox imbalance in hSCs, as evidenced by increased LDH and MDA levels and decreased GSH (all P<0.001), along with elevated c-Jun and NGFR expression (P<0.001). RSL3 produced a stronger lipid peroxidation response and similar repair-marker changes. Conditioned medium derived from these cells enhanced migration and invasion of OSCC cells (P<0.001), without affecting cell viability. Fer-1 treatment partially reversed these changes, reducing oxidative stress, suppressing repair-marker expression (P<0.001), and attenuating the pro-migratory and pro-invasive effects (P<0.001).

Conclusions: These findings support lipid peroxidation as a contributory regulator of Schwann cell repair-associated remodeling and suggest that redox modulation may attenuate Schwann cell-mediated PNI-like behavior in OSCC in vitro.