Hspa8, also known as HSC70, is a constitutively expressed, cognate protein of the HSP70 family. It is central in many cellular processes, especially playing a decisive regulatory role in autophagy. It is involved in protein quality control, ensuring proper protein folding and the elimination of abnormal proteins. Additionally, it participates in pathways like Wnt/β -catenin signaling, and is associated with various biological processes and diseases [2,5].

Hspa8 has been shown to have multiple functions through different studies. In anti -bacterial autophagy, it binds to RHOB and BECN1, preventing their degradation and driving liquid -liquid phase separation to concentrate these proteins, thus enhancing protein interaction and stabilization for intracellular bacteria clearance [1]. As an amyloidase, it specifically recognizes and disassembles RHIM -containing functional amyloids to suppress necroptosis signaling in cells and mice [3]. In liver cancer, HBx -induced Hspa8 enhances HBV replication and suppresses ferroptosis, promoting liver cancer progression [4]. In BRAF V600E colorectal cancer, Hspa8 promotes CMA -dependent degradation of CAV1, activating the Wnt/β -catenin pathway and contributing to cancer metastasis and progression [5]. In cholangiocarcinoma, RPL35A promotes cancer progression by mediating Hspa8 ubiquitination [6]. Down -regulation of lncRNA MAGI2 -AS3 decreases H2O2 content and delays cell senescence by stabilizing the Hspa8 protein level [7]. In sperm formation, BAG5 forms a complex with Hspa8 and promotes the folding of SPATA6 for sperm head -tail coupling apparatus assembly [8]. Hspa8 inhibitors can potentiate necroptosis, enhancing cancer cell sensitivity to microtubule -targeting agents and facilitating tumor regression in vivo [9].

In conclusion, Hspa8 is a multifunctional protein with essential roles in autophagy, protein folding, and multiple disease -related processes such as anti -bacterial defense, cancer progression, and cell senescence. Studies using in vivo models like mouse models (implied by in vivo experiments in references) have been crucial in revealing these functions, providing insights into potential therapeutic strategies for related diseases.