REG3A: A Multifunctional Antioxidant Lectin at the Crossroads of Microbiota Regulation, Inflammation, and Cancer

TL;DR

REG3A is a versatile protein involved in gut immunity, inflammation, and cancer, with both protective and tumor-related functions.

Contribution

This review provides a comprehensive overview of REG3A's diverse roles in immunity, inflammation, and cancer, highlighting its dual functions.

Findings

REG3A protects tissues from oxidative stress and regulates gut microbiota and immune responses.

REG3A can either promote or suppress tumor growth depending on the tumor type and environment.

Its secreted nature allows both local and systemic effects, influenced by organ-specific physiology.

Abstract

REG3A, a key member of the human REG lectin family, plays a multifaceted role in immunity, inflammation, and cancer. Primarily expressed in gastrointestinal epithelial cells, it reinforces gut barrier integrity, preserves mucosal immunity, and regulates host–microbiota interactions. Beyond its antimicrobial functions, REG3A acts as a targeted non-enzymatic antioxidant, protecting tissues from oxidative damage. Its expression is tightly regulated by inflammatory signals and is markedly upregulated during immune activation, where it limits microbial invasion, reduces tissue injury, and promotes repair. While REG3A offers critical protection in inflammatory settings, its role in cancer is far more complex. Depending on the tumor type and microenvironment, REG3A can either support tumor growth or exert tumor-suppressive effects. This review highlights the multifaceted biology of REG3A, with a focus on its roles in epithelial defense, immune modulation, oxidative stress regulation, and its paradoxical functions in cancer.

REG3A, a prominent member of the human regenerating islet-derived (REG) lectin family, plays a pivotal and multifaceted role in immune defense, inflammation, and cancer biology. Primarily expressed in gastrointestinal epithelial cells, REG3A reinforces barrier integrity, orchestrates mucosal immune responses, and regulates host–microbiota interactions. It also functions as a potent non-enzymatic antioxidant, protecting tissues from oxidative stress. REG3A expression is tightly regulated by inflammatory stimuli and is robustly induced during immune activation, where it limits microbial invasion, dampens tissue injury, and promotes epithelial repair. Beyond its antimicrobial and immunomodulatory properties, REG3A contributes to the resolution of inflammation and the maintenance of tissue homeostasis. However, its role in cancer is highly context-dependent. In some tumor types, REG3A fosters malignant progression by enhancing cell survival, proliferation, and invasiveness. In others, it acts as a tumor suppressor, inhibiting growth and metastatic potential. These opposing effects are likely dictated by a combination of factors, including the tissue of origin, the composition and dynamics of the tumor microenvironment, and the stage of disease progression. Additionally, the secreted nature of REG3A implies both local and systemic effects, further modulated by organ-specific physiology. Experimental variability may also reflect differences in methodologies, analytical tools, and model systems used. This review synthesizes current knowledge on the pleiotropic functions of REG3A, emphasizing its roles in epithelial defense, immune regulation, redox homeostasis, and oncogenesis. A deeper understanding of REG3A’s pleiotropic effects could open up new therapeutic avenues in both inflammatory disorders and cancer.

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