# Insights Into Macrophage Polarization and M1/M2 Balance in Diabetic Foot Ulcers

## TL;DR

This review explores how imbalanced macrophage types in diabetic foot ulcers hinder healing and suggests new treatment strategies to correct this imbalance.

## Contribution

A novel hierarchical network model of macrophage polarization signaling in DFUs, identifying NF-κB and JAK–STAT as key hubs.

## Key findings

- Persistent M1 macrophage dominance in DFUs causes chronic inflammation and poor healing.
- Pharmacological agents like insulin and ON101 cream can modulate macrophage polarization.
- NF-κB and JAK–STAT are central regulatory pathways in macrophage polarization.

## Abstract

Macrophage polarization, encompassing classically activated (M1) and alternatively activated (M2) states, is a critical determinant of immune response in wound healing. In diabetic foot ulcers (DFUs), a persistent imbalance favoring pro‐inflammatory M1 over anti‐inflammatory M2 macrophages drives chronic inflammation and impedes tissue repair. This review delineates the central role of macrophage polarization in DFU pathogenesis and systematically summarizes the key signaling pathways that govern this process, including PI3K/AKT, PPARγ, Notch, and Toll‐like receptors (TLRs). We further synthesize these cascades into a novel hierarchical network model, identifying NF‐κB and JAK–STAT as the core regulatory hubs. Beyond mechanism, we discuss emerging therapeutic strategies—including pharmacological agents and biomaterial‐based approaches—that target macrophage polarization, positioning them as promising adjuvants to standard wound care. By integrating mechanistic insights with therapeutic potential, this review provides an updated framework for developing targeted immunomodulatory therapies to break the cycle of non‐healing in DFUs.

This review elucidates the pivotal role of macrophage polarization in the pathogenesis of diabetic foot ulcers (DFUs), highlighting the contrasting functions of M1 and M2 macrophages in inflammation.We examine critical signaling pathways, including the NF‐κB and JAK–STAT pathways, that govern macrophage polarization in diabetic infections.Furthermore, we explore therapeutic strategies aimed at modulating these polarization states, offering innovative approaches for DFU treatment.Our findings provide valuable insights into potential interventions for improving outcomes in patients with DFUs.

This review elucidates the pivotal role of macrophage polarization in the pathogenesis of diabetic foot ulcers (DFUs), highlighting the contrasting functions of M1 and M2 macrophages in inflammation.

We examine critical signaling pathways, including the NF‐κB and JAK–STAT pathways, that govern macrophage polarization in diabetic infections.

Furthermore, we explore therapeutic strategies aimed at modulating these polarization states, offering innovative approaches for DFU treatment.

Our findings provide valuable insights into potential interventions for improving outcomes in patients with DFUs.

This graphical abstract illustrates pharmaceutical agents that modulate M1/M2 macrophage polarization in diabetic foot ulcers (DFUs). M1 macrophages (red) drive inflammation, whereas M2 macrophages (blue) promote tissue repair. In DFUs, persistent M1 predominance contributes to chronic non‐healing. Five key agents targeting this imbalance are depicted: insulin, AFG/GelMA hydrogel, genipin, Quercetin, and ON101 cream. These agents exert their effects through mechanisms including enhancement of M2 polarization, anti‐inflammatory activity, and modulation of critical signaling pathways (e.g., NF‐κB, JAK–STAT), thereby offering potential immunomodulatory strategies to improve DFUs healing.