Narrative review explores macrophage reprogramming for liver fibrosis and MASH

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Frontiers in Medicine Published May 17, 2026 Medically reviewed May 17, 2026 Study authors: Jorge Benjamin Aquino DOI ↗ By Dr. Julia Lee, PhD · Oncology, Genomics & Drug Development

Key Takeaway

Consider that macrophage reprogramming for liver fibrosis is preclinical; no clinical recommendations yet.

This is a narrative review that surveys macrophage reprogramming strategies for treating liver fibrosis, MASH, and other chronic liver diseases. The authors discuss a range of approaches including gene modulation, pharmacological agents, immunometabolic reprogramming, nanotechnology-based delivery systems, and cell-based therapies. The review synthesizes preclinical and early-stage evidence, highlighting the potential of targeting macrophage polarization and function to modulate fibrogenesis and inflammation.

Key findings are qualitative, as no pooled effect sizes are reported. The authors describe how reprogramming macrophages from a pro-inflammatory to a restorative phenotype may reduce fibrosis and improve liver histology. However, the review does not provide specific efficacy data, sample sizes, or comparator outcomes, reflecting the nascent stage of this field.

Limitations are not explicitly stated in the source, but as a narrative review, it lacks systematic methodology and quantitative synthesis. The absence of clinical trial data means practice relevance is currently limited to research contexts. No safety or tolerability information is reported.

Clinicians should recognize that these strategies are investigational. While conceptually promising, macrophage reprogramming for liver fibrosis remains in preclinical or early translational phases, and no clinical recommendations can be drawn at this time.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

Chronic liver diseases represent a major global health burden, with fibrosis as the common pathological outcome of sustained hepatic injury. Once considered irreversible, liver fibrosis is now recognized as a dynamic and potentially reversible process driven by complex cellular and molecular interactions within the hepatic microenvironment. Among these, hepatic macrophages have emerged as central regulators of both fibrogenesis and fibrosis resolution due to their remarkable phenotypic and functional plasticity. This review integrate experimental, translational, and emerging clinical evidence to propose macrophage reprogramming as a unifying therapeutic framework for liver fibrosis. A broad spectrum of intervention strategies -including gene modulation, pharmacological agents, immunometabolic reprogramming, nanotechnology-based delivery systems, and cell-based therapies- converges on promoting restorative macrophage phenotypes across toxic, metabolic, cholestatic, and inflammatory liver diseases. Particular emphasis is placed on key signaling and metabolic circuits -such as NF-κB, STAT1/3/6, PPARα/γ, AMPK, mitochondrial function, and autophagy- that collectively govern macrophage fate and function. The context-dependent nature of macrophage responses is highlighted, underscoring critical differences between toxic injury models (e.g., CCl4) and chronic metabolic conditions such as MASH, where macrophage heterogeneity and immunometabolic dysregulation impose additional therapeutic challenges. Emerging clinical data indicate that many antifibrotic strategies -despite distinct primary targets- converge on shared pathways of macrophage modulation, reinforcing their role as integrative hubs linking inflammation, metabolism, and tissue repair. Collectively, current findings indicate that durable fibrosis regression is unlikely to be achieved through single-target interventions. Instead, effective therapeutic strategies will require coordinated, temporally defined modulation of macrophages alongside other hepatic cells populations. Elucidation of the hierarchy and timing of macrophage-driven repair processes will be essential for the rational design of next-generation antifibrotic interventions with improved clinical efficacy.