# Lysophosphatidylcholine acyltransferase 1 promotes head and neck squamous cell carcinoma progression by enhancing COX17-dependent oxidative phosphorylation

## TL;DR

This study shows that LPCAT1 promotes head and neck cancer by boosting mitochondrial energy production through COX17, offering new therapeutic and diagnostic possibilities.

## Contribution

The novel finding is that LPCAT1 drives HNSCC progression via COX17-dependent oxidative phosphorylation.

## Key findings

- LPCAT1 is upregulated in HNSCC and its depletion reduces tumor growth and cell survival.
- LPCAT1 enhances mitochondrial function by regulating COX17 and Cytochrome c oxidase activity.
- Tissue levels of saturated fatty acyl-phosphatidylcholines may serve as early diagnostic biomarkers for HNSCC.

## Abstract

Metabolic dysregulation is increasingly recognized as a driver of tumor progression, yet its specific role in head and neck squamous cell carcinoma (HNSCC) remains poorly characterized. This study integrated untargeted metabolomics of HNSCC patient tissues with multi-omics validation to identify key metabolic alterations. We discovered a significant accumulation of sn-2 saturated fatty acyl-phosphatidylcholines, implicating disrupted phospholipid remodeling in HNSCC pathogenesis. Analysis of The Cancer Genome Atlas and Human Protein Atlas databases revealed consistent upregulation of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in HNSCC. This finding was further validated at mRNA, protein, and tissue levels by quantitative PCR, western blotting, and immunohistochemistry, respectively. Functional assays demonstrated that LPCAT1 knockdown suppressed tumor cell proliferation, migration, and invasion while increasing cell death in vitro, and inhibited tumor growth in nude mouse xenograft models. Mechanistically, LPCAT1 depletion impaired mitochondrial oxidative phosphorylation by reducing Cytochrome c oxidase activity, thereby decreasing ATP production. Our data further demonstrate that LPCAT1 regulates the expression of COX17, suggesting that the promotion of Cytochrome c oxidase activity and tumor bioenergetics by LPCAT1 is mediated through COX17. Thus, LPCAT1 drives HNSCC progression via a COX17-dependent metabolic reprogramming pathway. Targeting LPCAT1 represents a promising therapeutic strategy, while tissue-saturated fatty acyl-phosphatidylcholines may serve as early diagnostic biomarkers for HNSCC.