# A Novel Autophagy Inhibitor p-Hydroxylcinnamaldehyde Suppresses Esophageal Squamous Cell Carcinoma by Targeting LDHA Phosphorylation-Mediated Metabolic Reprogramming

## TL;DR

A new compound called p-hydroxylcinnamaldehyde (CMSP) was found to stop the growth of esophageal cancer by blocking autophagy and glucose metabolism.

## Contribution

The study introduces a novel autophagy inhibitor, CMSP, that targets LDHA phosphorylation to suppress ESCC through metabolic reprogramming.

## Key findings

- CMSP induces apoptosis in ESCC cell lines and patient-derived organoids by disrupting autophagic flux.
- CMSP inhibits LDHA phosphorylation, reducing lactate production and lysosomal acidity.
- In vivo studies show CMSP's potential for clinical application in ESCC treatment.

## Abstract

Autophagy is integral to the rapid proliferation of esophageal squamous cell carcinoma (ESCC), and its regulation presents a promising avenue for therapeutic intervention. Recent studies have elucidated the interplay between autophagy and glucose metabolism, while there is a paucity of anticancer drugs that concurrently target these 2 biological processes. In this study, we identified a natural compound, p-hydroxylcinnamaldehyde (CMSP), originally isolated from Cochinchina momordica seed (CMS) by our research team, which exhibits substantial anticancer activity against ESCC in both in vitro and in vivo models. The study demonstrates that CMSP induces apoptosis in ESCC cell lines and patient-derived organoid (PDO) models by disrupting autophagic flux. Mechanistically, CMSP specifically binds to the glycolytic enzyme LDHA in the cytoplasm, hindering its phosphorylation by blocking its membrane translocation and thereby disrupting its interaction with FGFR1. This inhibition results in decreased lactate production from glycolysis, reduced lysosomal acidity, and suppression of the AMPK/mTOR pathway, ultimately resulting in the blockade of autophagy and the induction of apoptosis. Furthermore, in vivo studies underscore the potential clinical application of CMSP in ESCC by disrupting autophagy. In summary, we propose a novel therapeutic strategy for the precision treatment of ESCC by simultaneously targeting glycolysis-mediated autophagy.