Abstract. Mutations in the Ky gene are the underlying cause of Myofibrillar Myopathy-7 (MFM-7), a rare progressive muscle weakness disease of childhood ons

Read the full paper: Aptamer-ROTAC assembled DNA nanocentipede for specific targeting of HSPA8 in hepatocellular carcinoma therapy

(Cell Reports 44, 115339; March 25, 2025)

Read the full paper: HSPA8 orchestrates SNARE complex assembly to drive extracellular vesicle-mediated spread of p-tau217 in Alzheimer's disease

Background Dysregulation of multivesicular bodies (MVBs) in Alzheimer’s disease (AD) contributes to aberrant tau secretion via extracellular vesicles (EVs). This may potentially explain our previous p...

Read the full paper: HSPA8 globally modulates transcriptome profile and PI3K/AKT signaling pathway to facilitate malignant progression phenotypes of triple-negative breast cancer

Published in Proceedings of the National Academy of Sciences of the United States of America

Khairallah et al., investigate the host proteins associated with a strong neutralizing antibody response to SARS-CoV-2. High neutralizing antibody responses to SARS-CoV-2 are associated with specific ...

Read the full paper: A new candidate tumor suppressor tRF-Ser inhibits gastric cancer progression by regulating the CNBP/HSPA8 axis

Read the full paper: OXCT1-induced Succinylation at K81 Shields HADH from HSPA8-Mediated Degradation in alveolar epithelial cells to Attenuate Lung Ischemia-Reperfusion Injury

Genes & Immunity - Hspa8 modulation of immune responses mitigates ischemic brain injury

La dégénérescence maculaire liée à l'âge pourrait être freinée et combattue en stimulant un mécanisme naturel de "nettoyage" des cellules de l'œil. Une équipe internationale de scientifiques dirigée p...

The autosomal dominant p.Ala165Val mutation in LIM Domain Binding Protein 3 (LDB3) causes myofibrillar myopathy marked by Z-disc disruption, accumulation of filamin-C (FLNc) and chaperone proteins,…

Publication date: September 2025 Source: Biomedical Technology, Volume 11 Author(s): Shuxin Zhong, Dingrui Nie, Xueting Peng, Kangjie Qiu, Jinyi Liu, Zhangshuai Dai, Xianfeng Zha, Songnan Sui, Weini Li, Weizhang Wang, Cunte Chen, Yangqiu Li, Chengwu Zeng

Yang et al. disclose that HSPA8, a molecular chaperone, identifies PKR and enlists CHIP to promote PKR ubiquitination and degradation. Subsequently, PKR phosphorylates INSIG and leads to SREBP activation, thereby controlling lipid metabolism. Short-term…

Our experimental evidence supports a model in which ALO targets the HSPA8-CMA-ATP6V1A axis to induce lysosomal hyperacidification and initiate osmotic and lipidomic stress. These changes are associated with LMP and loss of lysosomal integrity in prostate cancer cells. ABSTRACT Prostate cancer (PCa) ranks among the most common and deadly malignancies worldwide. The clinical treatment of advanced prostate cancer is particularly challenging due to acquired drug resistance. Autophagy and lysosome-related pathways are key drivers of this resistance. Targeting the lysosome represents a potential therapeutic strategy for PCa. In this study, we identified Heat Shock Protein Family A Member 8 (HSPA8) as a critical functional node of Aloperine (ALO). ALO suppresses autophagic flux, disrupts lysosomal homeostasis, and induces lysosomal vacuolation in cancer cells by inhibiting the function of HSPA8, impairing chaperone-mediated autophagy (CMA)-mediated ATP6V1A degradation. The resulting pathological accumulation and enhanced V1-V0 association of the V-ATPase complex drive pronounced lysosomal hyperacidification and severe osmotic swelling. This biochemical and physical stress is associated with lysosomal membrane permeabilization (LMP) and downstream loss of lysosomal integrity. Furthermore, we reveal that ALO-induced vacuolation triggers a compensatory upregulation of cholesterol biosynthesis to buffer membrane expansion; preemptively disrupting this adaptive response with the DHCR7 inhibitor AY9944 yields significant synergistic lethality. Collectively, our findings reveal the specific cytotoxic mechanism of ALO and demonstrate that pharmacological targeting of the HSPA8-CMA-ATP6V1A axis is a valuable strategy for inducing lethal lysosomal vacuolation in advanced PCa.

Triple-negative breast cancer has a poor prognosis. Pristimerin shows anti-tumor effects by activating autophagy and apoptosis. It directly targets HSPA8, leading to VAV1 degradation and activation of the MAPK/ERK pathway. In addition, it enhances TNBC cell sensitivity to doxorubicin and inhibits cell migration and invasion, suggesting its potential as a therapeutic agent against TNBC. Abstract Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis. The natural compound pristimerin has shown promising anti-tumor effect. Here, it is found that pristimerin significantly triggered the activation of autophagy initiation and induced apoptosis in TNBC. Mechanistically, RNA sequencing revealed that pristimerin activated mitogen-activated protein kinase/extracelluar regulated protein kinases (MAPK/ERK) pathway. Drug affinity responsive target stability and mass spectrometry techniques are employed to confirm the direct binding target of pristimerin. Heat shock protein family A member 8 (HSPA8) is identified and verified by cellular thermal shift assays and surface plasmon resonance assays. The further results suggested that pristimerin promoted the ubiquitination and degradation of HSPA8, leading to a decrease in the degradation of Vac Guanine Nucleotide Exchange Factor 1 (VAV1), a downstream client protein of HSPA8 which plays a crucial role in activating the ERK pathway. Importantly, knockdown of HSPA8 or VAV1 significantly impaired the anticancer activity of pristimerin on TNBC cells. Additionally, pristimerin significantly inhibited the migration and invasion of TNBC cells and enhanced the sensitivity of TNBC cells to doxorubicin. Collectively, this study provides the initial evidence that pristimerin directly targets HSPA8 to activate the VAV1/ERK pathway, thereby promoting cell autophagy and apoptosis.

Upregulated heat shock 70 kDa protein 8 (HSPA8) predicts poor prognosis of BRAF V600E colorectal cancer. HSPA8 interacts with Caveolin-1 at the KIFSN motif, leading to Caveolin-1 degradation and the subsequent β-catenin nuclear translocation. The Wnt/β-catenin pathway is then activated to promote metastasis. Notably, HSPA8 inhibitor VER155008 sensitizes BRAF V600E colorectal cancer to targeted drugs, which offers potential therapeutic strategies. Abstract BRAF V600E attracts wide attention in the treatment of colorectal cancer (CRC) as stratifying and predicting a refractory classification of CRC. Recent evidence indicates that Wnt/β-catenin signaling is broadly activated and participates in the refractoriness of BRAF V600E CRC, but the underlying molecular mechanism needs to be elucidated. Here, heat shock 70 kDa protein 8 (HSPA8), an essential regulator in chaperone-mediated autophagy (CMA), is identified as a potential therapeutic target for advanced BRAF V600E CRC. These results show that HSPA8 is transcriptionally upregulated in BRAF V600E CRC, which promotes CMA-dependent degradation of caveolin-1 (CAV1) to release β-catenin into the nucleus and thus activates the Wnt/β-catenin pathway, contributing to metastasis and progression of BRAF V600E CRC. Of note, HSPA8 directly interacts with the KIFSN motif on CAV1, the interaction can be enhanced by p38 MAPK-mediated CAV1 S168 phosphorylation. Furthermore, pharmacological targeting HSPA8 by VER155008 exhibits synergistic effects with BRAF inhibitors on CRC mouse models. In summary, these findings discover the important role of the HSPA8/CAV1/β-catenin axis in the development of refractory BRAF V600E CRC and highlight HSPA8 as a predictive biomarker and therapeutic target in clinical practice.