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Updated: Jan 9, 2026

Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
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OPRK1 drives SLC9A3R1 progression to neuroendocrine prostate cancer

Linghui Liang1, Zhiyi Shen2, Yuwei Zhang3

  • 1Department of Urology, Affiliated Wuxi No.2 Hospital, Nanjing Medical University & Jiangnan University Medical Center, Wuxi, Jiangsu, China.

Cell Death & Disease
|December 6, 2025
PubMed

Insights

Opioid receptor K1 (OPRK1) drives neuroendocrine prostate cancer (NEPC) progression by degrading REST. Targeting OPRK1 offers a new strategy against treatment-resistant prostate cancer (PCa).

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Neuroendocrine differentiation (NED) in prostate cancer (PCa) leads to therapy resistance and poor outcomes.
  • Treatment-induced NEPC (t-NEPC) emerges with androgen receptor pathway inhibitors (ARPIs), but its mechanisms are unclear.

Purpose of the Study:

  • Investigate the role of OPRK1 in t-NEPC development.
  • Elucidate the molecular pathway linking OPRK1 to NED.
  • Identify OPRK1 as a potential therapeutic target for PCa.

Main Methods:

  • Correlation analysis of OPRK1 levels and PCa prognosis.
  • Investigation of AR regulation of OPRK1 transcription.
  • Exploration of OPRK1's role in REST degradation and NED induction via SLC9A3R1 and autophagy.
  • Preclinical testing of OPRK1-targeting agents (JTC-801) combined with CQ.

Main Results:

  • Elevated OPRK1 levels correlate with t-NED and poor prognosis in PCa.
  • Androgen receptor (AR) represses OPRK1 transcription; ARPIs reverse this.
  • OPRK1 stimulation promotes NED by triggering autophagic degradation of REST via interaction with SLC9A3R1.
  • Combined JTC-801 and CQ treatment inhibited NEPC progression by targeting the OPRK1/SLC9A3R1/autophagy/REST axis.

Conclusions:

  • OPRK1 is a key mediator of ARPI-induced NEPC.
  • The OPRK1/SLC9A3R1/autophagy/REST pathway is crucial for t-NED.
  • OPRK1 represents a promising therapeutic target for overcoming treatment resistance in prostate cancer.

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