Lyssavirus Matrix Protein Stabilizes RGS4 to Suppress Ferroptosis via Incomplete Autophagy and Iron Metabolic Reprogramming [RABV-infected cells with DGAT activity]

However, the mechanistic link between LD formation and ferroptosis regulation during RABV infection remains poorly defined. Here, we report that RABV upregulates Regulator of G Protein Signaling 4 (RGS4), a ferroptosis-associated biomarker, and this induction is strictly dependent on triglyceride synthesis and subsequent LD formation.

Functionally, genetic or pharmacological inhibition of RGS4 elevates ferroptosis susceptibility, thereby restricting viral replication. Mechanistically, RGS4 depletion reduces expression of the E3 ubiquitin ligase HERC2, impairing K63-linked ubiquitination of Nuclear Receptor Coactivator 4 (NCOA4) and enhancing NCOA4 stability. Stabilized NCOA4 promotes ferritinophagy, leading to degradation of ferritin heavy chain (FTH) and ultimately inducing ferroptosis.