# Targeting NXPH4/ALDH1L2 signaling suppresses enzalutamide resistance in prostate cancer

## TL;DR

This study identifies NXPH4 and ALDH1L2 as key players in prostate cancer resistance to enzalutamide and suggests targeting them could improve treatment outcomes.

## Contribution

The study reveals a novel mechanism of enzalutamide resistance involving the NXPH4-ALDH1L2 complex and identifies it as a potential therapeutic target.

## Key findings

- NXPH4 promotes prostate cancer progression by reprogramming mitochondrial metabolism.
- NXPH4 interacts with ALDH1L2, a key enzyme in one-carbon metabolism.
- Combining NXPH4 knockdown with enzalutamide treatment synergistically inhibits tumor growth.

## Abstract

While androgen receptor (AR) pathway inhibitors such as enzalutamide have demonstrated significant therapeutic efficacy in prostate cancer (PCa) treatment, the inevitable development of acquired resistance continues to pose a major clinical challenge in managing advanced PCa. We characterized Neurexophilin 4 (NXPH4) as a contributor to enzalutamide resistance (EnzR). Gain- and loss-of-function studies were conducted in PCa cell lines and mouse subcutaneous xenograft models to elucidate the role of NXPH4 in castration-resistant prostate cancer (CRPC). Additionally, the regulatory mechanisms of gene expression were assessed using a series of molecular and biochemical experiments. Our study demonstrates that AR as a transcriptional activator of NXPH4. Elevated NXPH4 expression facilitated PCa proliferation under enzalutamide treatment through mitochondrial metabolic reprogramming. We identified that NXPH4 partially localizes to mitochondria and physically interacts with aldehyde dehydrogenase 1 family member L2 (ALDH1L2), a critical enzyme in one-carbon metabolism. Androgen deprivation stimulated NXPH4 mitochondrial translocation and enhanced its binding to ALDH1L2. NXPH4-mediated metabolic reprogramming promotes PCa progression. Notably, the combination of NXPH4 knockdown and enzalutamide treatment showed potent synergistic effects, significantly suppressing cell proliferation in vitro and substantially inhibiting tumor growth in vivo. These findings reveal a previously unrecognized mechanism of EnzR and identify the NXPH4-ALDH1L2 complex as a promising therapeutic target for CRPC treatment.