Antifibrotic mechanism of curcumin and its therapeutic potential in multi-organ diseases

Fibrosis is the outcome of chronic diseases and manifests as an abnormal repair process in which normal parenchyma is progressively replaced by deposited extracellular matrix. It leads to organ dysfunction and is associated with high morbidity, disability, and mortality, thereby becoming a major public health concern. Traditional Chinese medicine shows multi-target, multi-pathway strategies with favorable safety profiles. Curcumin (CUR), a polyphenolic metabolite derived from Curcuma longa L. (Zingiberaceae), has been shown to modulate key fibrotic signaling pathways, including AMPK, autophagy, extracellular-regulated protein kinase (ERK), transforming growth factor β (TGF-β)/Smad, JNK, and Wnt/β-catenin. However, a critical analysis of more than 200 included studies reveals that the current evidence base is fundamentally descriptive rather than conclusive. The data show reproducible antifibrotic signals in acute chemical injury models (bleomycin (BLM), carbon tetrachloride (CCl₄), and streptozotocin (STZ) when CUR is administered prophylactically. The data do not show (1) efficacy in chronic, progressive disease models that recapitulate human pathology; (2) a dose-response relationship linking achievable tissue concentrations to antifibrotic effects; (3) superiority over or an add-on benefit to standard-of-care antifibrotics; or (4) robust clinical efficacy beyond small, uncontrolled case series. Despite this promising preclinical evidence supporting CUR's antifibrotic efficacy, clinical translation remains constrained by several critical limitations. The majority of evidence derives from in vitro studies using supraphysiological concentrations that far exceed achievable human plasma levels and from animal models that incompletely recapitulate the chronic, progressive nature of human fibrotic diseases. Additionally, the inherently poor oral bioavailability of CUR-despite advances in formulation strategies-remains a persistent obstacle. A critical appraisal of the existing literature further reveals substantial heterogeneity in experimental designs, a predominance of positive results suggestive of publication bias, and insufficient mechanistic validation to establish causality. This review outlines the mechanisms of action, safety, adverse effects, drug interactions, and the application of CUR-related nanocomposite products, thereby providing a foundation for in-depth research on its antifibrotic properties and clinical application.