# TRIM16: a context-dependent E3 ligase in autophagy, oxidative stress, and immune regulation – from cancer and systemic disease

## TL;DR

TRIM16 is a versatile E3 ligase that regulates autophagy, stress, and immunity, acting as both a tumor suppressor and promoter depending on the context.

## Contribution

This review integrates recent findings to clarify TRIM16's context-dependent roles and therapeutic potential across multiple diseases.

## Key findings

- TRIM16 regulates oxidative stress and autophagy via the p62-KEAP1-NRF2 axis and lysophagy.
- TRIM16 acts as a tumor suppressor in most solid tumors but promotes pancreatic and hepatocellular carcinomas.
- TRIM16 protects against neurodegenerative and inflammatory diseases through quality control mechanisms.

## Abstract

TRIM16 is an atypical tripartite motif (TRIM) family E3 ligase that retains catalytic activity via its RING-like B-box domains, functioning primarily as a versatile molecular scaffold. This architecture enables TRIM16 to coordinate key cellular processes. These include oxidative stress responses (via the p62-KEAP1-NRF2 axis), secretory autophagy, lysophagy, and immune regulation, which collectively maintain cellular homeostasis. Emerging evidence highlights TRIM16 as a context-dependent regulator whose functions are shaped by cell type and microenvironment. In cancer, it acts as a tumor suppressor in most solid tumors by degrading oncoproteins and inducing cell cycle arrest, yet can paradoxically promote progression in pancreatic and hepatocellular carcinomas. Beyond oncology, TRIM16 protects against neurodegenerative, cardiovascular, and inflammatory diseases through quality control mechanisms. This review integrates recent advances to elucidate TRIM16’s molecular mechanisms and disease-specific functions, emphasizing its therapeutic and biomarker potential, and outlines future directions to decode its context-dependent actions for clinical translation.