Pathological lipid droplets interacting with lysosomes drive Hsp70 palmitoylation and redistribution, causing lysosomal impairment and astrogliosis in ischemic stroke, identifying Hsp70 palmitoylation as a potential drug target.
Lipid droplet signal and lysosomal cathepsin B leakage progressively increased after ischemia/reperfusion in mice.
Inhibiting fatty acid β-oxidation with etomoxir worsened I/R-induced LD accumulation and lysosomal damage in glial cells.
Exogenous LDs derived from OGD/Re-treated glial cells aggravated lysosomal damage and promoted proliferation of astrocytes and microglia.
LD accumulation was associated with Hsp70 palmitoylation and redistribution of Hsp70 from lysosomes to the extracellular space.
The LD surface protein Plin3 interacts with lysosomal Hsp70, causing its palmitoylation, redistribution, and lysosomal damage.
Extracellular Hsp70 activates TLR2/4 on glial cells, promoting proliferation and pro-inflammatory cytokine release.
Hsp70 palmitoylation is proposed as a potential drug target for ischemic stroke therapy.
This study looked at why support cells in the brain (astrocytes and microglia) become damaged and overactive after a stroke. Using a mouse model of stroke and cell culture models that mimic oxygen and glucose loss, the researchers found that fat-storing structures called lipid droplets build up in these cells over two weeks after stroke. At the same time, lysosomes (the cell's recycling compartments) became leaky, releasing the enzyme cathepsin B. Blocking fat burning with etomoxir made both problems worse. The researchers traced a pathway linking the two. A protein on the lipid droplet surface, Plin3, interacts with a protective protein, Hsp70, in lysosomes. This leads to Hsp70 being chemically modified by palmitoylation (attachment of a fatty acid) and moved out of lysosomes into the space outside cells. Lysosomes are then damaged, and Hsp70 outside the cell activates immune receptors (TLR2/4) on glial cells, driving their proliferation and inflammatory signaling. This research suggests that Hsp70 palmitoylation could be a target for future stroke treatments. The work is based on mouse and cell models, so it does not show whether such an approach would work in people.
Ma Y, Liu Y, Du H, Xu Y, Ni Y, Zhang H. (2026). Lipid Droplet-Associated Hsp70 Palmitoylation Drives Lysosomal Dysfunction in Ischemic Stroke.. Neurochemical research. https://doi.org/10.1007/s11064-026-04933-1