Fibroblast PI3K/AKT signaling and extracellular matrix homeostasis: mechanisms, targets, and delivery challenges

TL;DR

This paper explores how fibroblast PI3K/AKT signaling influences extracellular matrix homeostasis and its role in various tissue-related processes and diseases.

Contribution

The study integrates multi-tissue insights to unify understanding of PI3K/AKT signaling in fibroblasts, aiding precision therapeutic design.

Findings

PI3K/AKT signaling in fibroblasts modulates extracellular matrix homeostasis and affects key cellular processes.

The pathway is linked to fibrotic diseases, wound healing, and tissue remodeling through metabolic and stress responses.

A unifying framework is proposed to address fibroblast heterogeneity and guide targeted therapies.

Abstract

The extracellular matrix (ECM) is essential for tissue homeostasis, ensuring structural stability, facilitating cell-cell communication, and tightly controlling key cellular processes, including proliferation, differentiation, and migration. Numerous cell types and signalling cascades direct ECM turnover; chief among them, the phosphatidyl-inositol-3-kinase (PI3K)/AKT (protein kinase B, PKB) axis remains intensively studied in fibroblasts. Recent evidence indicates that the integration of extracellular cues with intracellular mediators in fibroblasts can modulate the impact of the PI3K/AKT pathway on the ECM. This process is intricately linked to critical fibroblast functions such as metabolic reprogramming, autophagy, apoptosis, and stress responses, ultimately shaping outcomes in fibrotic diseases, wound healing, tissue remodelling, and pathological scar formation. Whereas conventional reviews centre on site-restricted subsets in single disorders, we integrate multi-tissue insights to chart PI3K/AKT signalling across heterogeneous fibroblast populations, taxonomising their sources into a unifying framework that confronts heterogeneity and accelerates precision therapeutic design.

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