# ALDH3A2 negatively orchestrates gastric cancer progression through a synergistic induction of ferroptosis and ferroptosis-driven macrophage reprogramming

## TL;DR

ALDH3A2 suppresses gastric cancer by inducing cell death and reprogramming immune cells, offering a new therapeutic target.

## Contribution

ALDH3A2 is newly identified as a dual regulator of ferroptosis and macrophage reprogramming in gastric cancer.

## Key findings

- ALDH3A2 overexpression reduces cancer cell proliferation and induces ferroptosis.
- ALDH3A2 impairs mitochondrial function by blocking NRF2 and downregulating SLC47A1.
- ALDH3A2-induced ferroptosis promotes M1 macrophage polarization and inhibits tumor progression.

## Abstract

Gastric cancer (GC) is a prevalent gastrointestinal malignancy in which ferroptosis, mitochondrial dysfunction, and macrophage reprogramming remarkably contribute to disease progression. However, the molecular interplay among these processes in contributing to GC remains poorly understood. In this study, we identified ferroptosis- and mitochondrial dysfunction-related genes (FMDRGs) implicated in GC through bioinformatics analyses. Among them, aldehyde dehydrogenase 3 family member A2 (ALDH3A2) was identified as a key FMDRG significantly downregulated in GC tissues and cell lines. Functional assays revealed that ALDH3A2 overexpression in GC cell lines suppressed proliferation, migration, and invasion while enhancing ferroptosis, effects that were reversed by GPX4 overexpression. ALDH3A2 also impaired the mitochondrial unfolded protein response (UPRmt) and induced mitochondrial dysfunction. Restoration of UPRmt ameliorated ALDH3A2-induced mitochondrial dysfunction and ferroptosis. Mechanistically, ALDH3A2 impaired UPRmt by downregulating SLC47A1 through blockade of NRF2 nuclear translocation, leading to mitochondrial dysfunction, GPX4 downregulation, lipid peroxidation, and subsequent ferroptosis. Synergistically, ALDH3A2-induced ferroptosis promoted IL-6 release, which drove macrophage polarization toward the M1 phenotype with elevated IL-1β production. This macrophage reprogramming, in turn, inhibited GC cell progression by downregulating PD-L1 expression. Therapeutically, both genistein treatment and ALDH3A2 overexpression significantly attenuated GC progression in vitro and in vivo. These findings elucidate ALDH3A2 as a dual regulator of tumor-intrinsic ferroptosis and tumor-extrinsic immune remodeling in contributing to GC pathogenesis, highlighting its potential as a promising therapeutic target in GC.