HSPA9 (Heat Shock Protein Family A (Hsp70) Member )

This study established an AI-based radiomics system for identifying HCC patients with poor prognosis associated with high expression of GRP75, and revealed a novel therapeutic approach utilizing the TCM monomer baicalin to reverse multi-drug resistance through GRP75 targeting, further clarifying its mechanism.

In this review, we summarize the contribution of mitochondrial and endoplasmic reticulum (ER) stress in the pathogenesis of epithelial ovarian cancer along with their role as potential biomarkers and therapeutic targets, including proteins of glucose metabolism, mitochondrial fission and fusion, mitophagy, membrane-associated ring-CH-type finger 5 (MARCH5), A-kinase anchoring proteins (AKAPs), proteins regulating mitochondrial Ca2+ homeostasis, mitochondrial unfolded protein response (UPRmt) proteins, activating transcription factors (ATFs), CCAAT enhancer binding protein (C/EBP) homologous protein (CHOP), 'mitokines', GRP75, and GRP78. Although many of these potential targets are in preclinical phase, they have a high potential to become valuable alternative or additive treatments for epithelial ovarian cancers.

In xenograft and spontaneous models, combined HBO-TKIs treatment delays tumor progression and modulates the HNF4A/RCN1 axis. Taken together, our findings elucidate a hitherto uncharacterized role of HBO in regulating ER-mitochondria calcium homeostasis and support its clinical application as an adjunctive therapy in TKI-resistant HCC.

Crucially, dual targeting of lipid metabolism (with statins) and mechanotransduction (with GsMTx4) resensitizes PCa to chemotherapy by normalizing ECM architecture and restoring MERCs integrity. Our work defines the "mechanometabolic niche" as a targetable signaling hub where coordinated lipid metabolism and TME biomechanics converge to dictate therapeutic response and unveils a novel co-targeting strategy for advanced PCa.

This review summarizes the development of HSP70 inhibitors into three distinct chemical strategies: (1) pan-HSP70 inhibitors that target the conserved ATPase domain shared across isoforms; (2) isoform-selective inhibitors that address specific HSP70 family members; and (3) protein-protein interaction inhibitors that disrupt functional chaperone complexes. This review has systematically linked the structural analysis of HSP70 (including its structure and co-chaperone networks), disease-associated signaling pathways, and pathological roles to establish a classification framework based on its four major subtypes (HSP70i, HSC70, GRP78, and GRP75).

Importantly, pharmacological inhibition of USP1 with ML323 effectively enhances PTCL cell sensitivity to doxorubicin, suggesting a promising therapeutic strategy to improve treatment outcomes in PTCL patients. Collectively, we have found that USP1 represents a compelling therapeutic target for addressing chemoresistance and improving outcomes in PTCL therapy.

Tumor-derived Cav-1 promotes ROS-dependent ferroptosis in MDSCs via PKA-DRP1-mediated ER-mitochondrial crosstalk, causing the release of oxidized phosphatidylcholines that suppress T-cell function and promote an immunosuppressive TME. Targeting this axis may improve the response of breast cancer patients to immunotherapy.

These findings underscore the therapeutic relevance of targeting ferroptosis in cancer, particularly by leveraging TFRC's role in iron homeostasis. Furthermore, this study expands the understanding of post-translational regulation in ferroptosis, offering a new perspective on the role of artesunate in cancer therapy.

Finally, via drug screening and functional analysis, we innovatively revealed a traditional Chinese medicine monomer, luteolin, which could prevent B[a]P-induced abnormal DR and hepatic fibrosis by targeting GRP75. Our study offers new insights into environmental toxin-induced hepatobiliary diseases and suggests a potential key interventional target or approach for the prevention of abnormal DR.

Therefore, future research should aim to increase antigen specificity, optimize vaccine formulations, and explore combinatory regimens to overcome resistance mechanisms in cancer cells. Overall, GRP-targeted vaccines represent a very compelling candidate in cancer immunotherapy with great potentials for clinical translation in the future.

Finally, we revealed that targeting GRP75 with stearic acid (SA) could prevent DEHP-induced CP-ADM via drug screening and functional analysis. Our present study offers new insights into environmental toxin-induced pancreatic disorders and suggests a potential key intervention target for the prevention of CP-ADM.

Collectively, these data support mortalin as a potential therapeutic target for oral cancer and warrant further studies for the development of mortalin-targeting drugs in both laboratory and clinical settings.