Fear stress promotes glioma progression through inhibition of ferroptosis by enhancing FSP1 stability

Purpose: Patients diagnosed with Cancer often suffer from emotional stressors, such as anxiety, depression, and fear of death. However, whether fear stress could influence the glioma progression is still unclear.

Methods: Xenograft glioma animal models were established in nude mice. Tumor-bearing mice were subjected to fear stress by living closely with cats and then their depressive behaviors were measured using an open field test. Hematoxylin and eosin staining, the TUNEL staining and immunochemical staining were used to detect the histopathological changes of tumor tissues. Gene expression profiling was used to screen the aberrant gene expression. Methylated RNA immunoprecipitation was used to identify the RNA m⁶A level. Gene expression was measured by western blot and Real-Time PCR, respectively.

Results: We found that fear stress promoted glioma tumor progression in mice. Fear stress-induced upregulation of METTL3 and FSP1, increased m⁶A level of glioma tumor tissues, and inhibited Ferroptosis in glioma progression, which were reversed by knockdown of METTL3 and FSP1 in vivo. In addition, we found that when iFSP1 (a Ferroptosis inducer by targeting inhibition of FSP1) was introduced to glioma cells, the cells viability of glioma significantly was decreased and Ferroptosis was enhanced in glioma cells.

Conclusions: Fear stress-induced upregulation of METTL3 stabilized FSP1 mRNA by m⁶A modification, leading to tumor progression through inhibition of Ferroptosis. Our study provides a new understanding of psychological effects on glioma development, and new insights for glioma therapy.

FSP1and METTL3; Fear stress; Ferroptosis; Glioma; m6A.