# METTL5 in physiology and pathology: mechanisms and implications

## TL;DR

This review explores METTL5's role in regulating translation through RNA modification and its implications in development and cancer.

## Contribution

The paper provides a comprehensive overview of METTL5's physiological and pathological roles, emphasizing its potential as a cancer biomarker and therapeutic target.

## Key findings

- METTL5 modifies 18S rRNA, influencing ribosome function and selective mRNA translation.
- METTL5 is essential for embryonic development, stem cell fate, and cardiac function.
- Aberrant METTL5 expression correlates with cancer progression and poor prognosis.

## Abstract

METTL5, in complex with TRMT112, catalyzes N6-methyladenosine (m6A) at A1832 of 18S rRNA, acting as a novel regulator of translational control. This modification within the ribosomal decoding center modulates ribosome assembly and selective mRNA translation. Physiologically, METTL5 is required for embryonic and neural development, stem cell fate, spermatogenesis, and cardiac function. Aberrant expression has been reported in multiple cancers, where it correlates with poor prognosis. Mechanistically, METTL5 drives proliferation, metastasis, and chemoresistance by promoting oncogenic translation, reprogramming metabolism, regulating ferroptosis, and shaping the immune microenvironment. Cooperation with m6A readers, including IGF2BP and YTHDF proteins, contributes to these effects. Targeting METTL5 shows therapeutic promise, with compounds such as salvianolic acid C and scutellarin demonstrating inhibitory activity. In this review, we summarize the molecular characteristics, physiological roles, and pathological functions of METTL5, highlight its mechanisms in tumorigenesis and immunity, and discuss its potential as a biomarker and therapeutic target.