Inhibiting HSP27 activates the XBP1s/CerS1 interplay, which triggers DRP1-driven mitophagy, thereby protecting against cell death and promoting the KSHV lytic cycle in primary effusion lymphoma cells.

PEL is an aggressive B-cell lymphoma that in the majority of cells harbors latent KSHV, although appropriate stimuli can induce viral replication. These include HDAC inhibitors such as butyrate, activation of endoplasmic reticulum (ER)/UPR stress, and exogenous administration of ceramide 18. These treatments reduce cell survival, but also activate adaptive branches of the UPR such as the Ire1α-XBP1s axis and/or trigger macroautophagy to counteract cell death, processes whose output may be manipulated by KSHV. HSPs are also upregulated by several cytotoxic treatments and support both cell survival and KSHV replication, suggesting a complex relationship between cell and viral fate. In this study, we demonstrate that HSP27 inhibition reduces PEL cell survival, activates ER stress including XBP1s, and upregulates CerS1, the enzyme that synthesizes ceramide 18. We further discovered a crosstalk between XBP1s and CerS1 that enhances protection against ER stress during HSP27 inhibition also promoting DRP1-dependent pro-survival mitophagy and triggers KSHV reactivation from latency. In conclusion this study suggests that HSP27 plays a previously unrecognized central role in controlling the UPR, CerS1 and mitochondrial autophagy, influencing both cell survival and KSHV lytic cycle in PEL cells.