Heat shock protein Gp96 (Grp94) in malaria: functional insights at the host-parasite interface and therapeutic perspectives

Heat shock protein Gp96 (also known as Grp94 or endoplasmin) is the endoplasmic reticulum (ER)-resident paralog of the Hsp90 family and a central regulator of ER proteostasis and immune receptor biogenesis in mammalian cells. By controlling the folding, quality control, and trafficking of a restricted yet functionally critical set of client proteins, including Toll-like receptors, integrins, and immunoglobulins, Gp96 plays an essential role in innate immunity and inflammatory signaling. In the context of malaria, accumulating evidence suggests that host-derived Gp96 is involved in immune activation and disease severity, notably through its extracellular release under conditions of cellular stress, where it functions as a danger-associated molecular pattern (DAMP). Elevated circulating Gp96 levels have been associated with severe malaria phenotypes, supporting its potential value as a biomarker of host stress and immune dysregulation. In parallel, Plasmodium falciparum expresses its own ER-resident Hsp90 homolog, PfGp96, which retains the conserved domain architecture of Hsp90 while exhibiting parasite-specific adaptations, including divergence in ER retention motifs. However, the biological functions, client repertoire, and essentiality of PfGp96 remain poorly defined, and direct evidence supporting its validation as a drug target is currently limited. This review critically synthesizes current knowledge on Gp96 and PfGp96, emphasizing experimentally validated functions, host-parasite interface dynamics, and unresolved knowledge gaps. We discuss the opportunities and challenges of targeting Gp96-related pathways for biomarker development and therapeutic intervention in malaria, while outlining key priorities for future functional and translational research.