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Targeting the HSPA8-CMA-ATP6V1A Axis Triggers Lysosomal Hyperacidification and Catastrophic Vacuolation in Prostate
Bingzheng An1, Ze Gao1, Shuo Chen2
1Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 19, 2026
Summary
Aloperine (ALO) targets Heat Shock Protein Family A Member 8 (HSPA8) to disrupt lysosomal function in advanced prostate cancer (PCa). This induces lethal vacuolation, offering a new therapeutic strategy for drug-resistant PCa.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Advanced prostate cancer (PCa) presents significant treatment challenges due to acquired drug resistance.
- Autophagy and lysosome-related pathways are implicated as key mechanisms driving this resistance.
- Targeting lysosomal function offers a promising therapeutic avenue for PCa.
Purpose of the Study:
- To elucidate the specific cytotoxic mechanism of Aloperine (ALO) in advanced PCa.
- To identify Heat Shock Protein Family A Member 8 (HSPA8) as a critical functional node for ALO's action.
- To evaluate the therapeutic potential of targeting the HSPA8-CMA-ATP6V1A axis.
Main Methods:
- Investigated ALO's effect on cancer cell autophagy and lysosomal homeostasis.
- Assessed the role of HSPA8 in ALO-induced lysosomal dysfunction and vacuolation.
- Examined the impact of ALO on V-ATPase complex, lysosomal pH, and membrane integrity.
- Evaluated the synergistic effect of combining ALO with a DHCR7 inhibitor (AY9944).
Main Results:
- ALO inhibits HSPA8, impairing chaperone-mediated autophagy (CMA)-mediated ATP6V1A degradation.
- This leads to lysosomal accumulation, hyperacidification, osmotic swelling, and lysosomal membrane permeabilization (LMP).
- ALO-induced vacuolation upregulates cholesterol biosynthesis; inhibiting this pathway synergistically enhances lethality.
Conclusions:
- ALO induces cancer cell death by triggering lethal lysosomal vacuolation via HSPA8 inhibition.
- Targeting the HSPA8-CMA-ATP6V1A axis represents a novel strategy for treating advanced, drug-resistant PCa.
- Combination therapy with DHCR7 inhibitors may enhance ALO's efficacy.
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