# Lactate metabolism and protein lactylation in colorectal cancer: from metabolic reprogramming to epigenetic regulation

## TL;DR

This paper explores how lactate metabolism and protein lactylation contribute to colorectal cancer progression and proposes a new therapeutic framework targeting these processes.

## Contribution

The study introduces a unified lactate–lactylation axis and proposes a three-step therapeutic framework for colorectal cancer.

## Key findings

- Excessive lactate accumulation in CRC promotes immune suppression and therapeutic resistance.
- Lactate serves as a substrate for lysine lactylation, linking metabolism to epigenetic regulation.
- A three-step therapeutic framework targeting lactate metabolism and lactylation is proposed.

## Abstract

Colorectal cancer (CRC) exhibits profound metabolic reprogramming, in which excessive lactate accumulation remodels the tumor microenvironment and promotes immune suppression, angiogenesis, and therapeutic resistance. Recent studies reveal that lactate also serves as a substrate for lysine lactylation (Kla), linking metabolic overflow to epigenetic regulation. This review focuses on CRC but also incorporates mechanistic data from other tumor models when CRC-specific evidence is limited, synthesizing lactate metabolism, transport, and lactylation into a unified lactate–lactylation axis. Mechanistic analyses highlight the roles of glycolytic enzymes, monocarboxylate transporters (MCT1/4–CD147), and Kla writers, erasers, and readers in driving malignant progression. Based on these insights, a three-step therapeutic framework is proposed: lowering lactate production, blocking lactate shuttling, and restraining Kla-mediated transcriptional reprogramming. Biomarker-guided evaluation using serum lactate dehydrogenase (LDH), tissue Kla immunohistochemistry, and hyperpolarized [1-^13C]-pyruvate MRI provides translational feasibility. This axis offers a mechanistic basis and actionable targets for metabolism-driven precision therapy, particularly in microsatellite-stable CRC (MSS CRC).