Fig. 8: This diagram delineates the regulatory role of USP14 in GPX4-mediated anti-ferroptotic defense, which contributes to radioresistance in HCC. | Cell Death & Disease

Fig. 8: This diagram delineates the regulatory role of USP14 in GPX4-mediated anti-ferroptotic defense, which contributes to radioresistance in HCC.

From: Targeting the TRIM14/USP14 axis enhances radiotherapy efficacy by inducing GPX4 degradation and disrupting ferroptotic defense in HCC

Fig. 8

Radiation prompts the interaction of TRIM14 with GPX4, recruiting USP14 into the complex. USP14 subsequently cleaves K48-linked polyubiquitin chains from GPX4 at lysine 48 or 118, thereby counteracting radiation-induced ubiquitination that would otherwise target GPX4 for degradation. By stabilizing GPX4 and preserving its antioxidant activity, USP14 suppresses radiation-triggered ferroptosis. Pharmacological inhibition of USP14 significantly sensitizes HCC cells to radiation-induced ferroptosis while also potentiating the immune response elicited by radiotherapy, ultimately enhancing therapeutic efficacy.

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