Work

PLIN2 links lipid droplets to GRP78-mediated GPX4 stabilization to suppress neuronal ferroptosis

Year: 2026

Type: article

Abstract: Neuronal ferroptosis is increasingly recognized as a major driver of neuroinflammation, yet how lipid droplets coordinate neuronal antioxidant defense remains largely unknown. Here, we identify a previously unrecognized PLIN2-GRP78 pathway that links lipid droplets to the ferroptosis regulator GPX4. Mechanistically, the lipid droplet protein PLIN2 directly interacts with GRP78, promoting its expression and translocation from the endoplasmic reticulum (ER) to the cytosol. Cytosolic GRP78 subsequently associates with GPX4, preventing its K48-linked ubiquitination and proteasomal degradation, thereby preserving GPX4 stability and limiting lipid peroxidation, reactive oxygen species accumulation, and ferroptotic cell death. Furthermore, overexpression of PLIN2 failed to restore GPX4 expression or alleviate ferroptosis in GRP78-deficient neurons, indicating that GRP78 is required for the anti-ferroptotic function of PLIN2 and that PLIN2 regulates ferroptosis through the GRP78-GPX4 axis. Importantly, neuron-specific deletion of GRP78 markedly exacerbates ferroptosis, microglial activation, inflammatory cytokine production, and mortality in both lipopolysaccharide (LPS)-induced and virus-induced neuroinflammation, whereas pharmacological inhibition of ferroptosis largely reverses these pathological changes. Together, our findings establish a mechanistic link between lipid droplets and the GPX4 antioxidant system through PLIN2-dependent regulation of GRP78, revealing an unreported pathway controlling neuronal ferroptosis and neuroinflammation and highlighting GRP78-mediated GPX4 stabilization as a potential therapeutic strategy for neuroinflammatory diseases.

Source: Cell Insight

DOI: 10.1016/j.cellin.2026.100369