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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
PubMed

Insights

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.
Keywords:
HSPA8V‐ATPasechaperone‐mediated autophagylysosomal membrane permeabilizationosmotic stress

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