Fibrotic disease is a widespread disease that critically threatens public health, mainly including pulmonary fibrosis, liver fibrosis, renal fibrosis, myocardial fibrosis, peritoneal fibrosis, and other diseases. It has been widely reported to be characterized by high morbidity and mortality (Olson et al., 2007; Pottier et al., 2014). 45% of mortality in developed countries is related to cumulative impairment of tissue-specific function and final organ dysfunction due to fibrosis (Nanthakumar et al., 2015). It is noteworthy that with the acceleration of the aging of population, the above situation will become increasingly serious, and the morbidity and mortality rates will continue to increase (Redente et al., 2011; Kurundkar and Thannickal, 2016). Fibrosis is the procedure of aberrant aggregation of ECM after different types of tissues being damaged. It is a pathological stage of poor repair of all organs and tissues (Henderson et al., 2020; Panizo et al., 2021). Current treatment strategies for fibrotic diseases have many obstacles, including the lack of cell or tissue specificity of anti-fibrotic treatments, the occurrence of adverse events of anti-fibrotic drugs, and limited treatment options (Ramachandran and Henderson, 2016; Nastase et al., 2018; Lamb, 2021). Over the past decade, despite increasing research in the management of fibrotic diseases, its illness and death rate have continued to increase. Therefore, the development of anti-fibrotic therapeutic strategies holds substantial clinical importance. Traditional Chinese medicine (TCM) has a long history which has played a decisive status in the evolution of medicine in China for more than 2,000 years. Existing evidence shows that herbal medicine can serve as an important supplement and alternative method for anti-fibrotic drug treatment (Li et al., 2021; Li et al., 2022). It has the advantages of wide source, low toxicity, and structural diversity (Shan et al., 2019).

Turmeric (Curcuma longa L., Linnaeus, Zingiberaceae) is the rhizome of a perennial herbaceous plant of the ginger family, mainly distributed in southern and southwestern tropical Asia region (Aggarwal et al., 2007; Kocaadam and Şanlier, 2017). In TCM, turmeric was first documented in “New Materia Medica” (Hu Chenxia, 2008). It has the effects of invigorating blood circulation, and relieving depression (Qin et al., 2022). In clinical practice, turmeric is commonly used in a variety of herbal formulas to treat a wide array of diseases and body pathologies (Yang et al., 2019; Wu Yuhong and Liu, 2020; Zhengtao et al., 2022). Curcumin, a phenolic compound isolated from turmeric in modern times, is the main active ingredient responsible for the therapeutic effects of turmeric (Esatbeyoglu et al., 2012; Priyadarsini, 2014). Curcumin is often used as a pigment and spice in food, cosmetics, and textiles to dye and enhance flavor. It can also treat multi-system diseases (Aggarwal et al., 2007; Kocaadam and Şanlier, 2017; Qin et al., 2022), such as dermatologic diseases, infection, stress, and depression. Research on various diseases has proven that curcumin has anti-inflammatory, antioxidant, anti-cancer, antibacterial, anti-parasitic, anti-viral, and immune-modulating effects (Prasad et al., 2014; Kotha and Luthria, 2019; Zheng et al., 2020; Abd El-Hack et al., 2021; Luo et al., 2023). Different concentrations of curcumin have no obvious toxic effects on normal tissues and cells (Aggarwal and Harikumar, 2009). Therefore, curcumin is widely used in clinical research on various diseases.

Curcumin, a lipophilic polyphenolic compound with low molecular mass, demonstrates significant therapeutic efficacy alongside a favorable safety profile. Numerous studies have proved the anti-fibrotic traits of curcumin, primarily in the lung, liver, kidney, and myocardial fibrosis (Kong et al., 2020; Sadoughi et al., 2021) (Figure 1). The mechanism may be related to inhibiting extracellular matrix (ECM) deposition, oxidative stress, and alveolar epithelial cells (AEC) cell apoptosis, reducing inflammatory response, and enhancing autophagy (She et al., 2018; Hernández-Aquino et al., 2020; Fathimath Muneesa et al., 2022; Cui et al., 2023). Among them, oxidative stress plays an important role in the initiation and development of fibrosis by damaging lipids, proteins, and DNA, inducing cell necrosis and apoptosis, amplifying inflammatory responses, stimulating the production of pro-fibrotic mediators, etc (Sánchez-Valle et al., 2012). This article reviews the mechanism of curcumin’s anti-fibrosis effects by inhibiting oxidative stress, to provide a reference for subsequent research.

A comprehensive online search of literature was conducted via Web of Science, Google Scholar, and China National Knowledge Infrastructure, covering 2000 until 2024. The ensuing key concepts were utilized: Curcumin, Turmeric Yellow, Curcumin Phytosome, Diferuloylmethane, Oxidative Stress, Antioxidative Stress, Oxidative Damage, Oxidative Stress Injury, Oxidative Injury, Oxidative Cleavage, Oxidative DNA Damage, ROS, Oxidative and Nitrosative Stress, Oxidative Nitrative Stress, Nitro-Oxidative Stress, Fibrosis, Cicatrix, Fibrosing, Hypertrophic, Keloid, Tissue Adhesions, Cirrhosis, fibrillation, fibration and fibering. A comprehensive examination was also conducted on the bibliographies of all the articles obtained from the search, aiming to incorporate pertinent literature.

Curcumin serves as a natural compound sourced from Zingiberaceae plants, a vital group of medicinal plants (Shakeri et al., 2019). Generally speaking, curcumin can be extracted from the rhizomes or roots of ginger plants (Nan et al., 2023), which are customarily called turmeric (Curcuma) or turmeric in traditional Chinese medicine, respectively (Jianmin et al., 1983). An analysis of the rhizome or root extracts of ginger plants using thin-layer chromatography confirmed that the curcumin content in different plants of the same genus and even in rhizomes and roots of the same plant are significantly different (Jianmin et al., 1983). Qi et al. analyzed the curcumin content in the same species of ginger plants from different regions by HPLC and confirmed that the curcumin content was affected by the species of curcuma (Jianmin et al., 1983; Aidi and Wenyujin, 2002).

In 1953, Srinivasan determined the presence of curcumin and other components in turmeric by chromatography (Kocaadam and Şanlier, 2017). Most crude extracts prepared from turmeric mainly include curcumin (I), desoxymethylcurcumin (II), and dideoxymethylcurcumin (III) (Priyadarsini, 2014). The physicochemical properties of curcumin are presented in Table 1. It can be rapidly degraded when exposed to conditions including an alkaline pH environment (Dellali et al., 2021). Later, Chandrasekhara and Ravindranath et al. synthesized curcumin from vanillin and acetylacetone by condensation using the Pabon method with more than 99% content determined by the rose anthocyanin method (Ravindranath and Chandrasekhara, 1980; 1981a).

Pharmacokinetics is the study of drug absorption, distribution, metabolism, and excretion, which helps us evaluate the properties of specific drugs and their application prospects. At present, there are a large number of literature studies on metabolic process of curcumin in rats, which are mainly administered by intraperitoneal injection, sublingual vein, oral administration, or the pharmacokinetics of curcumin in rats (Holder et al., 1978; Wahlström and Blennow, 1978; Ravindranath and Chandrasekhara, 1980; 1981a; b; Wang et al., 1997). Wahlstrom et al. reported that plasma levels and bile excretion measurements showed malabsorption of curcumin from the intestine in Sprague-Dawley rats at an oral dose of 1 g/kg (Wahlström and Blennow, 1978). Ravindranath et al. used radioactive tritium-labeled drugs to evaluate the tissue distribution of curcumin. The outcomes demonstrated that when Sprague-Dawley rats were given oral curcumin doses of 400 mg, 80 mg, and 10 mg, the percentage of curcumin absorption did not change. This demonstrates a dose-dependent limitation in curcumin absorption bioavailability (Ravindranath and Chandrasekhara, 1981b). Once curcumin is absorbed, it undergoes conjugation effects at different tissue sites. Research has found that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are the main metabolites of curcumin in the body (Pan et al., 1999; Hoehle et al., 2006). Studies have shown that when rats are administered 100 mg/kg by intraperitoneal injection, curcumin levels are highest in the liver, followed by the spleen (Pan et al., 1999). However, in another human clinical study, 12 patients with colorectal cancer liver metastases received curcumin about 450–3,600 mg of per day 1 week before surgery. At the end, no curcumin was detected in the liver tissue, and only a small amount of reduced turmeric metabolites was detected (Garcea et al., 2004). Moreover, the rate at which curcumin is eliminated from the body serves as another crucial determinant of its biological impacts. Studies have shown that when Sprague-Dawley rats take an oral dose of 1 g/kg of curcumin, 75% of it is defecated in the feces, while the content of curcumin in the urine is negligible (Wahlström and Blennow, 1978). In another study, subsequent to the oral administration of a 400 mg dose of curcumin to rats, no traces of curcumin were discernible in their urinary samples (Ravindranath and Chandrasekhara, 1980). Metabolic studies using radiolabeled curcumin in rats, when administered at 400 mg/animal, about 40% of the unaltered form of curcumin was found in the feces (Ravindranath and Chandrasekhara, 1981b). Regardless of the dosage, the urinary excretion of curcumin is very low. The temporal parameters for the absorption and clearance phases of curcumin (2 g/kg) after oral ingestion in rats are 0.31 ± 0.07 and 1.7 ± 0.5 h respectively (Anand et al., 2007). One clinical study found that patients with advanced colorectal cancer who took turmeric extract orally everyday for 4 months contained 36–180 mg of curcumin and had neither curcumin nor curcuminoids in their urine metabolites (Sharma et al., 2001). Overall study results indicate that oral curcumin has low absorption and rapid clearance (Mirzaei et al., 2017). The above characteristics such as low bioavailability, short plasma half-life, low plasma concentration, and poor oral absorption have seriously limited the clinical development of curcumin (Tomeh et al., 2019; Hao et al., 2023). The study stated that when administered at the maximum recommended dose of 5 g/Kg, there was no obvious toxic effect on Sprague-Dawley rats (Wahlström and Blennow, 1978). Similarly, Aggarwal et al. studied the acute toxicological damage of curcumin-essential oil complex (CEC), an available biological agent, in rats and mice at the uppermost advised dose of 5,000 mg/kg. In contrast to the control group, these animals also showed no symptoms, toxicity, or death (Aggarwal et al., 2016). Findings from Phase I clinical trials involving curcumin indicate its safety in humans, even when administered at elevated doses (12 g/day) (Anand et al., 2007). However, more reliable research is needed to prove whether there is any difference in the toxic damage to internal organs and cells between animal and human bioavailable preparations.

The process of fibrosis involves excessive deposition of ECM and remodeling of the injured site, leading to the restoration of unnecessary connective tissue and organ dysfunction during the repair process (Lurje et al., 2023). It may be present in virtually all organs of the human organism, such as the liver, kidneys, heart, lungs, and skin. Repeated injury is a general characteristic of fibrotic diseases. There are different causes, such as chronic virus infection, autoimmune, chronic ischemia process, or toxicity (including nicotine, alcohol, drugs, or radiation) (Distler et al., 2019). Fibrosis begins with the triggering of parenchymal cell damage or death and is usually repetitive or persistent. The subsequent repair process is mediated by regulatory processes such as damage recognition, rapid myeloid attraction and fibroblast activation. However, they lack the capacity to restore physiological equilibrium (Lurje et al., 2023). These fibrosis are typically characterized by the chronic inflammatory response coupled with alterations in the invasive immune cell infiltrate (Guillot and Tacke, 2019). Endogenous early-phase proinflammatory mediators including IL-1, IL-6, TNF, and TGF-β derived from macrophages, tissue fibroblasts, and resident stromal populations drive the differentiation of IL-17-producing effector cells. IL-17A promotes tissue damage through the production of ROS that enhances the neutrophilic response and meanwhile increases the expression of TGF-β receptors on fibroblasts, thereby promoting ECM production in the TGF-β response (Henderson et al., 2020). Immune cell subsets further drive fibrotic progression through the release of angiopoietic and fibrogenic mediators that act on resident fibroblasts and vascular endothelial cells, thereby inducing pathological neovascularization, and promoting tissue damage by secreting matrix metalloproteinases and ROS (Pardo et al., 2016; Bartneck et al., 2019; Sutti et al., 2019).

In the pathological mechanism of oxidative stress-induced fibrosis, Oxidative stress drives inflammatory cascades via elevated secretion of proinflammatory cytokines and fibrogenic growth factors, thereby promoting myofibroblast activation and pathological extracellular matrix remodeling. ROS upregulates TGF-β signaling pathways and serve as critical effectors in propagating TGF-β-induced fibrogenic responses, including fibroblast activation, the synthesis of pro-fibrotic mediators, epithelial/endothelial cell apoptosis, and epithelial-mesenchymal transition (EMT) (Liu and Desai, 2015). On the other hand, increased extracellular matrix deposition due to oxidative stress subsequently leads to fibrosis (Jianming and Li, 2016; Makena et al., 2023). In the meanwhile, oxidative stress causes lipid damage to parenchymal cell membranes, disrupts enzyme and protein modifications that are essential for cell metabolism, and promotes DNA mutation, culminating in apoptosis of these cells. In summary, oxidative stress can cause the progress of fibrotic diseases through these damages (Antar et al., 2023) (Figure 2).

The present study systematically elucidates the multifaceted antifibrotic therapeutic mechanisms of curcumin (Figure 3).

In patients with non-alcoholic fatty liver disease (NAFLD), a randomized controlled trial (RCT) found that 12 weeks of curcumin supplementation (1,500 mg/day) significantly reduced hepatic fibrosis scores compared to baseline, although it was not superior to lifestyle modification alone in ameliorating systemic inflammation (Saadati et al., 2019). The disparity in outcomes underscores the potential need for longer intervention periods or more bioavailable formulations, a notion strongly supported by a 12-month RCT in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes, where 1,500 mg/day of curcumin led to significant reductions in both hepatic steatosis and liver stiffness, alongside marked improvements in systemic inflammation and oxidative stress (Yaikwawong et al., 2025).

The most compelling evidence for curcumin’s direct anti-fibrotic action in human tissue comes from a 72-week, double-blind RCT using the phospholipid formulation Meriva (2 g/day) in patients with biopsy-proven non-alcoholic steatohepatitis (NASH) (Musso et al., 2025). This study reported that a remarkable 42% of patients on Meriva achieved regression of significant liver fibrosis, with 62% experiencing NASH resolution, effects potentially mediated by the inhibition of hepatic NF-κB. Importantly, the same trial also observed a significant regression of concomitant chronic kidney disease in 50% of the Meriva group, suggesting systemic anti-fibrotic benefits (Musso et al., 2025). To specifically validate these findings in renal fibrosis, the large-scale, multicenter MPAC-CKD-1 trial was designed to evaluate the efficacy of a micro-particle curcumin formulation on albuminuria and estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease, with results anticipated to provide crucial evidence on its potential to slow disease progression (Weir et al., 2018).

Curcumin exhibits a broad spectrum of positive effects in mediating oxidative stress for therapeutic intervention in fibrotic diseases. In the present investigation, the molecular mechanism of curcumin-mediated oxidative stress against fibrotic diseases was reviewed, such as PPAR, NRF2, HO-1, TGF-β, AGE-RAGE, and other signaling pathways. Curcumin functions as a free radical scavenger through its phenolic substances, beta-diones, and methoxys, acting on the activity of ROS (Farzaei et al., 2018). In liver fibrosis, damage to liver cells causes the formation of apoptotic bodies (AB), the leakage of mitochondrial DNA, or the generation of ROS. These factors initiate the stimulation of Kupffer cells and the conversion of dormant hepatic stellate cells into myofibroblastic phenotypes. Leptin, Angiotensin II, TGF-β, Platelet-derived growth factor (PDGF), and other mediators help activate NOXs in macrophages and stellate cells and further accelerate matrix deposition. Reaserches have found that curcumin has shown prophylactic and curative effects on oxidization-related liver disease through multiple cells signaling cascades. These pathways include upregulated PPAR (Zhai et al., 2015; Elmansi et al., 2017; Kong et al., 2020), NRF2 (Liu et al., 2016; Gowifel et al., 2020) and HO-1 (Öner-İyidoğan et al., 2014) signaling pathways, and downregulated RAGE (Lin et al., 2012) and AGEs (Tang and Chen, 2014) signaling pathways. In pulmonary fibrosis, ROS generation contributes to fibroblast phenotype acquisition, including differentiation, contraction, apoptotic resistance, and ECM deposition (Hecker et al., 2009; Hosseinzadeh et al., 2018). Evidence suggests that curcumin can activate the protein kinase B (Akt)/Nrf2/HO-1 (Lee et al., 2010; Ke et al., 2020) signaling pathway and attenuate the TGF-β1, MPO (Li et al., 2019) and ROS (Kumari and Singh, 2022) to inhibit redox imbalance in pulmonary fibrosis models. In myocardial fibrosis, the cardiac source of ROS is mainly nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase (Li et al., 2002), which exacerbates cardiac fibrosis and modulates gap junction function, resulting in diminished myocyte coupling and facilitating arrhythmogenic reentry (Sovari, 2016). Curcumin reduces cardiac fibrosis by activating SIRT1, increasing NRF2 (Zeng et al., 2015), increasing NADPH oxidase subunits, weakening PKC-MAPK (Soetikno et al., 2012) signaling pathway, and reducing SOD and MDA (Sadoughi et al., 2021). In renal fibrosis, redox imbalance can cause the reduction of ATP production after mitochondrial dysfunction, and may also lead to the development of EMT in diabetic nephropathy, resulting in renal fibrosis (Lv et al., 2018). Emerging evidence indicates that curcumin attenuates renal fibrosis through Wnt/β-catenin (Ho et al., 2016), HO-1 (Zhang et al., 2015) and Nrf2-Keap1 (Soetikno et al., 2013) signaling pathways. These provide references for the pharmacology and clinical application of curcumin for therapeutic intervention in fibrotic diseases. However, there are some questions that need to be further clarified in future studies before this natural compound can be used clinically.

Synthesizing the evidence from liver, renal, myocardial, and pulmonary fibrosis, a coherent model for curcumin’s pleiotropic actions comes into focus. We propose a “Core Pathway - Specific Branch” model to conceptualize its effects. At the heart of this model lies the consistent activation of the Nrf2 antioxidant pathway and the concerted suppression of the TGF-β signaling axis. These two core pathways, addressing the universal pillars of oxidative stress and pro-fibrotic signaling, form the foundational mechanism of curcumin’s efficacy across all organs studied.

Firstly, human pharmacokinetics of curcumin remain incompletely characterized, with low absorption and fast metabolism (Mirzaei et al., 2017). Secondly, limited absorption of curcumin severely constrains its clinical utility. Fortunately, chemical modification of curcumin significantly enhances its therapeutic efficacy, target selectivity, and safety profile. In addition to this, sophisticated drug delivery platforms, including liposomes, nanoparticles, and phospholipid complexes formulated with diverse synthetic/natural biomaterials (proteins, lipids, polymers), have demonstrated enhanced bioavailability and formulation stability for curcumin derivatives. The promising work on phospholipid complexes and nanoparticles must be advanced towards “smart” targeted delivery. Strategies should include designing nanoparticles that home to activated stellate cells or profibrotic fibroblasts, engineered for stimulus-responsive release in the high-ROS microenvironment of the fibrotic niche. This would ensure precise spatiotemporal delivery, enhancing efficacy while minimizing off-target effects. Combining curcumin with established anti-fibrotic drugs in a single nano-formulation could also create powerful synergistic therapies, where curcumin acts as a “sensitizing” agent to enhance the primary drug’s efficacy. Although extensive research efforts have addressed formulation limitations and optimized physicochemical attributes, critical gaps persist in curcumin’s therapeutic efficacy, target specificity, and pharmacokinetic performance—issues that warrant urgent attention from the scientific community (Bisht et al., 2007). Third, due to the multi-target properties of curcumin, its anti-fibrosis mechanism has not been fully illustrated and more validation is needed. The majority of contemporary investigations primarily emphasize cellular and animal-based models, yet scarce clinical evidence exists to assess curcumin’s anti-fibrotic therapeutic potential and its corresponding dosage requirements. More studies should provide more conclusive evidence, especially those with large samples and multi-center prospective cohort studies. The most critical frontier is the design of definitive clinical trials. The scarcity of clinical evidence, highlighted earlier, must be addressed through hypothesis-driven, biomarker-enriched trials. These trials should incorporate. Validated Redox and ECM Biomarkers: Moving beyond standard serum enzymes to include direct markers of oxidative stress (e.g., specific lipid peroxidation adducts) and ECM turnover (e.g., PRO-C3) to objectively quantify anti-fibrotic efficacy. Precision Enrollment: Focusing on specific fibrotic disease etiologies and potentially stratifying patients based on their baseline redox or inflammatory status. Long-term Safety and Efficacy Assessment: Rigorously evaluating the long-term safety profile, a concern we previously raised, and the ability of curcumin to halt or reverse fibrosis progression in large-scale, multi-center, randomized controlled trials. Fourth, concerning safety evaluation, extended-duration human studies are required to rigorously evaluate the therapeutic safety profile of curcumin in clinical populations.

In summary, numerous investigations have validated that the anti-fibrotic effect of curcumin through mediating oxidative stress, and more studies are needed to further confirm the anti-fibrotic effect of curcumin. It is hoped that with further research, the therapeutic effect of curcumin on fibrotic diseases may be understood and applied clinically.