1 Introduction

Turmeric is a rhizomatous perennial herb belonging to the family Zingiberaceae and has been widely cultivated throughout South and Southeast Asia. Historical documents evidenced that turmeric has conventionally been used for more than 4 000 years, with its medicinal properties standing out in Ayurveda, Unani, and traditional Chinese medicine. Conventionally, turmeric rhizomes have been used traditionally for the treatment of wounds, digestive disorders, respiratory ailments, and various inflammatory diseases. In addition to its cultural and traditional importance, turmeric has received increasing global scientific interest because of its pharmacological activities with broad spectra: antioxidant, anti-inflammatory, antimicrobial, anti-cancer, and metabolic regulatory effects. Recent development in phytochemistry and molecular biology has catapulted turmeric into an exciting natural therapeutic agent against chronic diseases associated with inflammation and immune dysfunction (Zhang et al., 2024).

Curcumin, first isolated in the early 19^th century, is the most studied polyphenolic compound obtained from C. longa. It belongs to a class of diarylheptanoids known as curcuminoids, including demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC). The structural entity of curcumin consists of two feruloyl moieties linked by a conjugated heptadiene chain, giving it high electron-donating and radical-scavenging activity. This is the structure behind its interaction with multiple molecular targets, modulation of cascading, and consequent pleiotropic biological effects. Despite this multifunctional activity, curcumin is poorly soluble in aqueous media and hence shows low bioavailability. Hence, much effort has been made toward developing its improved formulations and delivery systems. The fast-growing understanding of the chemistry of curcuminoids has thus awakened interest in their possible therapeutic efficacy and mechanistic diversity (Kocaadam and Sanli̇er, 2017).

Chronic inflammation and immune dysregulation are among the principal causes of many pathological conditions, such as cancers, cardiovascular diseases, metabolic disorders like type 2 diabetes and obesity, and neurodegenerative diseases represented by Alzheimer's and Parkinson's diseases. Chronic inflammatory signaling in combination with uncontrollable cytokine production, oxidative stress, and inappropriate activation of immune cells all jointly contribute to tissue damage, disruption of metabolic homeostasis, and progression of a disease. Among central inflammatory pathways, NF-κB, MAPK, JAK/STAT, and NLRP3 inflammasome signaling have a place of prime importance in the onset and maintenance of these disorders. Given that they are complicated and multifactorial diseases, therapeutic approaches have increasingly required the capability for modulating multiple molecular targets in their course. Thus, natural compounds that may exert wide-ranging regulatory functions, such as curcumin and its analogs, have been increasingly focused upon in research (Cozmin et al., 2024).

This study gives a state-of-the-art overview of the anti-inflammatory and immunomodulatory effects of Curcuma longa and its major curcuminoids. We outline herein the chemical nature and bioactive components of turmeric; the molecular mechanisms by which curcumin modulates key inflammatory pathways and immune responses; findings from in vitro studies, animal models, and clinical research; factors affecting its bioavailability and metabolism, including interaction with the gut microbiota; and considerations about safety, therapeutic potential, and current challenges for clinical translation. This study synthesizes evidence at the molecular, cellular, and systemic levels and provides scientific insights that may be supportive of developing curcuminoid-based interventions for the prevention and management of chronic inflammatory and immune-related diseases.

2 Major Bioactive Components of Curcuma longa: Types and Chemical Properties

2.1 Curcumin and its derivatives

The main curcuminoid in turmeric is curcumin, which usually consists of 60%-70% of the total curcuminoids, followed by demethoxycurcumin and bisdemethoxycurcumin. All these curcuminoids have a diarylheptanoid skeleton, and the difference in methoxy group substitution changes the solubility and biological activity of these compounds. Curcumin is a hydrophobic polyphenol responsible for yellow coloration in turmeric and is highly recognized for possessing anti-inflammatory, antioxidant, and anticancer properties. Demethoxycurcumin and bisdemethoxycurcumin also present significant bioactivity, including anti-inflammatory and antiproliferative activity (Fuloria et al., 2022; Cozmin et al., 2024; Roney et al., 2024).

The main rhizome is referred to as “mother rhizome” or bulb, with a central pear shape (Figure 1). The lateral branches of mother rhizomes are referred to as secondary rhizomes, also called lateral or “finger rhizomes”. Mother rhizomes were more matured when compared to finger rhizomes, thus possessing higher concentrations of curcuminoids and probably higher essential contents than finger rhizomes. However, finger rhizomes bear a higher yield of curcumin when compared to mother rhizomes (Setzer et al., 2021).

Figure 1 The underground part of turmeric shows the rhizome and root (Adopted from Setzer et al., 2021)

2.2 Curcuminoids and other phenolic compounds

Besides the three major curcuminoids, turmeric contains other phenolic compounds such as tetrahydrocurcumin and curcuminol that contribute to its antioxidant and anti-inflammatory activities. Such phenolics can act as free radical scavengers and modulate various cellular pathways.

Turmeric essential oils are rich in sesquiterpenoids (ar-turmerone, α-turmerone, β-turmerone), monoterpenoids (α-phellandrene, 1,8-cineole), and other terpenoids. These volatile oils have been reported to possess antimicrobial, anti-inflammatory, and neuroprotective activities and, thus may improve the absorptive potential and efficacy of curcuminoids (Setzer et al., 2021).

It also contains minerals like potassium, calcium, iron, and phosphorus; trace amounts of vitamins; polysaccharides; flavonoids; alkaloids; and sterols, factors that enhance its nutritional value and, possibly, its therapeutic benefits (Fuloria et al., 2022; Roney et al., 2024).

2.3 Molecular basis of synergistic interactions among components

Recent studies show that mixtures of curcuminoids in their natural proportions have much greater biological activity compared with isolated compounds, reflecting synergy. Volatile oils may also potentiate curcuminoid bioavailability and influence various signaling pathways, further reinforcing the overall efficacy of turmeric extracts (Fuloria et al., 2022; Cozmin et al., 2024).

3 Curcuma longa and Curcumin: Mechanisms of Anti-inflammatory Effects

3.1 Inhibition of inflammatory signaling pathways (NF-κB, MAPK, JAK/STAT)

Curcumin potently suppresses several critical inflammatory signaling pathways, such as NF-κB, MAPK (p38, ERK, JNK), and JAK/STAT. It prevents NF-κB activation through IκBα stabilization and inhibits nuclear translocation; it also directly interferes with the DNA-binding domain of NF-κB p65. Curcumin suppresses the phosphorylation of MAPKs and inhibits STAT3 activation, which in turn broadly suppresses the expression of inflammatory genes (Kahkhaie et al., 2019; Ghany et al., 2023). These occur in a concentration-dependent and multi-cellular manner involving immune and epithelial cells.

It downregulates the synthesis and expression of the major pro-inflammatory cytokines, TNF-α, IL-1β, IL-6, and enzymes such as COX-2 and iNOS. This results in reduced synthesis of prostaglandins and nitric oxide, both central to the inflammatory response. These have been demonstrated in in vitro studies and in animal models of inflammation (Kahkhaie et al., 2019; Kim et al., 2022; Ghany et al., 2023).

3.3 Cross-talk between antioxidant and anti-inflammatory activities

Its antioxidant action is seriously interrelated with its anti-inflammation action. It activates the Nrf2/HO-1 pathway, enhances cellular antioxidant defense capacity, and decreases oxidative stress, leading to the suppression of NF-κB activation and its downstream inflammatory mediators. This cross-talk enhances the action of curcumin in controlling inflammation (Kim et al., 2022; Ghany et al., 2023).

Curcumin regulates apoptosis through the upregulation of anti-apoptotic proteins, such as Bcl-2; downregulation of pro-apoptotic factors, such as Bax and caspase-3; and preservation of mitochondrial integrity. Moreover, curcumin induces autophagy and suppresses the Akt/mTOR pathway, which promotes cell survival and diminishes inflammatory cell death (Guo et al., 2016).

Mechanistically, curcumin inhibits macrophage activation, thus dampening the production of pro-inflammatory cytokines while enhancing anti-inflammatory phenotypes, such as CD206 expression. Curcumin also represses dendritic cell maturation and cytokine release, modulating innate and adaptive immune responses (Fuloria et al., 2022; Nicoliche et al., 2024) (Figure 2).

Figure 2 The mechanism of curcumin in reducing inflammation,anabolic and apoptosis (Adopted from Fuloria et al., 2022)

4 Mechanisms of Immunomodulatory Effects of Curcuma longa and Curcumin

4.1 Modulation of innate immunity

It enhances the innate immune response by the activation of macrophages and increases the production of NO and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) by inducing the NF-κB pathway. Curcumin increases NK cytotoxicity, enhancing DC functioning, while at the same time suppressing excessive neutrophil recruitment and chemotaxis, balancing immun activation and inflammation (Memarzia et al., 2021; Kim et al., 2024).

4.2 Modulation of adaptive immunity

Curcumin may modulate adaptive immunity through the regulation of T and B lymphocytes' responses. It can affect T helper differentiation by downregulating Th1, Th2, and Th17, while upregulating regulatory T cells (Tregs). Curcumin also increases T follicular helper cell and germinal center B cell immune responses, which will account for better antibody productions and an improved humoral immunity (Kim et al., 2019; Haftcheshmeh et al., 2022; Zeng et al., 2022).

4.3 Regulation of inflammasomes and immune responses

Curcumin inhibits activation and assembly of the NLRP3 inflammasome-a critical driver of IL-1β and IL-18 production in inflamatory disease-via suppression of NF-κB and through interference with inflammasome components directly. This reduces the release of the downstream inflammatory cytokines and eventually exerts protective effects against tissue damage (Laurindo et al., 2023).

Curcumin modulates the PI3K/Akt/mTOR pathway at the center of immune cell proliferation, survival, and metabolism. It can suppress mTOR signaling, thereby inhibiting T cell activation and proliferation, and may modulate TLR4 and STAT pathways to achieve broad immunoregulatory effects (Xu et al., 2018; Wang et al., 2025).

4.4 Studies in immune-related disease models

Preclinical and clinical studies have established that curcumin and extracts of Curcuma longa exert favorable effects on models of autoimmune diseases-such as rheumatoid arthritis, multiple sclerosis, and ulcerative colitis-allergic diseases, and cancer-by modulating cytokine profiles, the activation of immune cells, and intracellular signaling pathways. There is evidence for improved effectiveness with nanomedicine formulations, as reported by Laurindo et al. (2023) and Haftcheshmeh et al. (2022).

5 In Vitro and In Vivo Research Progress of Curcuma longa and Curcumin

5.1 In vitro anti-inflammatory and immunomodulatory experiments

In vitro, Curcuma longa and curcumin have been observed to exert considerable anti-inflammatory and immunomodulatory effects. Various studies illustrate that curcumin suppresses the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, while inhibiting the biosynthesis of NO and the activity of iNOS in activated macrophages. All these effects result from the inhibition of major inflammatory pathways, including NF-κB and MAPKs in a variety of immune cell types (Pintatum et al., 2020; Memarzia et al., 2021).

5.2 Cellular-level signaling pathway analyses

Cell culture studies have shown that curcumin exerts its mechanisms through the disturbance of several signal transduction pathways involved in the critical regulation of inflammation and immune responses, such as NF-κB, MAPK, JAK/STAT, and PI3K/Akt/mTOR. The suppression of these pathways by curcumin leads to the inhibition of inflammatory mediators and immune cell function (Fuloria et al., 2022).

5.3 Pharmacological effects in animal models

In animal models of inflammation, autoimmune diseases, and metabolic disorders, in vivo studies with curcumin or extracts from Curcuma longa consistently demonstrate a decrease in the infiltration of inflammatory cells, a reduction in levels of cytokines, and the amelioration of symptoms. Such effects were observed in models of arthritis, colitis, diabetes, and wound healing, among others (Makuch et al., 2021; Memarzia et al., 2021).

Because of poor bioavailability, new formulation approaches for curcumin, including nanoparticles, liposomes, and micelles, have been developed. These advanced modes of delivery greatly enhance the absorption and therapeutic efficacy of curcumin in both preclinical and clinical settings (Kotha and Luthria, 2019).

5.4 Effects of extraction methods and processing techniques on bioactive content and activity

The various methodologies of extraction and processing, including microwave-assisted extraction, ultrasound-assisted extraction, and the use of natural deep eutectic solvents, influence both yield and composition related to the bioactive curcuminoids. Indeed, advanced technologies of extraction allow for an increase in the content of curcumin with enhanced bioactivity and enable better pharmacological applications (Singh et al., 2022; Jovanović et al., 2025).

6 Bioavailability and Metabolism of Curcuma longa and Curcumin

6.1 Gastrointestinal absorption, plasma concentration, and metabolic characteristics

Poor gastrointestinal absorption, due to the hydrophobic nature of curcumin, coupled with low solubility, leads to minimal plasma concentrations following oral administration. Most absorbed curcumin is extensively metabolized within the liver and intestinal mucosa to glucuronide and sulfate conjugates, representing predominant forms detected in plasma. The majority of orally ingested curcumin is excreted unmetabolized in feces, and its elimination half-life is short, further limiting systemic bioavailability (Purpura et al., 2017).

6.2 Effects of food matrix, dosage, and formulation on bioavailability

The bioavailability of curcumin heavily depends on the food matrix, dosage, and formulation. Co-administration with fats or oils increases absorption; however, at higher dosages, absorption becomes saturated, and rapid metabolism results in less than proportional increases in the plasma levels of the parent compound. Advanced formulation developments, such as nanoparticles, micelles, liposomes, phospholipid complexes, and cyclodextrin inclusion complexes, remarkably improve the solubility, stability, and absorption of curcumin, allowing higher and more sustained plasma concentrations compared to unformulated curcumin (Tabanelli et al., 2021; Hsu et al., 2025).

6.3 Strategies to improve bioavailability

Various approaches have been developed to overcome poor bioavailability: adjuvants such as piperine that inhibit curcumin metabolism, formulation with essential oils such as BCM-95®, and encapsulation in nanoparticles, micelles, or liposomes. Such approaches increase absorption, prolong plasma residence time, and enhance therapeutic efficacy. Piperine, for example, can enhance curcumin bioavailability by up to 2000%, while new water-soluble or cyclodextrin-based formulations have achieved several-fold higher plasma levels (Tabanelli et al., 2021; Hsu et al., 2025).

6.4 Role of metabolites in physiological activities

Therefore, curcumin undergoes extensive metabolism into conjugated forms, such as glucuronide and sulfate, and reduced forms like dihydrocurcumin and tetrahydrocurcumin. While these metabolites show, in some contexts, lesser activities compared to free curcumin, specific reduced metabolites retain or even increase antioxidant and anti-inflammatory activities. Their physiological relevance is currently under investigation since they could be responsible for the systemic effects of curcumin, even at the very low concentrations of its parental form (Cerullo et al., 2025; Hsu et al., 2025).

6.5 Gut microbiota-curcumin interactions and contribution to immune modulation

Curcumin interacts bidirectionally with the gut microbiota. The microbiota metabolizes curcumin into active derivatives, whereas curcumin modulates the composition and function of the gut microbiome toward increasing the abundance of beneficial bacteria while suppressing pathogenic species. These interactions can improve intestinal barrier function, reduce inflammation, and thus contribute to immune modulation. Actually, the gut microbiota-curcumin axis is increasingly recognized as one of the key factors explaining curcumin’s health effects at low systemic bioavailability (Tabanelli et al., 2021; Cerullo et al., 2025).

7 Safety, Dosage, and Current Clinical Research on Curcuma longa and Curcumin

7.1 Safety and toxicological studies of curcumin and Curcuma longa

Curcumin and Curcuma longa are generally recognized as safe for human consumption. Toxicological studies in animals show no mutagenic, genotoxic, or reproductive toxicity at standard doses, and acute oral LD50 values are high (>5,000 mg/kg in rats) (Zeng et al., 2022). Human studies have reported that oral curcumin is well tolerated up to 6-12 g/day for several weeks, with only mild gastrointestinal side effects in some cases (Zeng et al., 2022). According to EFSA, a derivative, tetrahydrocurcuminoids, is safe at 140 mg/d for adults (Turck et al., 2021).

7.2 Potential risks: Hepatotoxicity, drug interactions, etc.

While curcumin is generally considered safe, some very rare instances of hepatotoxicity have been reported, generally following the compound in supplement form at very high dosages or when given in combination with piperine, which enhances the bioavailability of curcumin and may potentially inhibit drug-metabolizing enzymes such as CYP3A4 or P-glycoprotein. Most adverse effects are mild and relate to gastrointestinal upset; caution is warranted in individuals with liver disease or those taking medications dependent on hepatic metabolism (Stati et al., 2021; Zahra et al., 2024).

7.3 Evidence and limitations of existing human clinical trials

Several RCTs and meta-analyses support the effectiveness and safety of curcumin and extracts from Curcuma longa for indications such as osteoarthritis, arthritis, and some autoimmune diseases, with efficacy comparable to NSAIDs but fewer adverse events. However, most are small, of short duration, and have variable formulations; as a result, results cannot be generalized, and optimal dosing cannot be established (Fuloria et al., 2022; Panknin et al., 2023). More high-quality clinical trials with larger samples are needed.

7.4 Regulation and application of functional foods and supplements

Curcumin is generally considered by regulatory agencies, such as the US FDA and EFSA, as a food additive and supplement, allowing an acceptable daily intake of 0-3 mg/kg body weight (Turck et al., 2021). It is now being widely used in functional foods, nutraceuticals, and supplements; however, challenges still exist concerning product quality and standardization.

Curcumin's poor bioavailability, rapid metabolism, and instability impede the pharmaceutical development of curcumin, despite promising preclinical and clinical data (Hassanzadeh et al., 2020; Jacob et al., 2024). Nanotechnology and various new formulations have been under study, but only a few are approved for use by regulatory agencies, and long-term safety of new delivery systems needs further investigation.

8 Concluding Remarks

During the last several decades, research into Curcuma longa and its principal curcuminoid, curcumin, has identified multifaceted biological activities relevant to inflammation and immune regulation. There is accumulating evidence from cell-based studies, animal models, and early-phase clinical investigations that curcumin has anti-inflammatory actions through modulating key molecular targets, including the NF-κB, MAPKs, JAK/STAT, and PI3K/Akt/mTOR pathways. In parallel, curcumin was shown to regulate innate and adaptive immune responses through modulation of macrophage polarization, T-cell differentiation, cytokine secretion, and inflammasome activation. Such cumulative data point to a comprehensive, mechanistically linked network whereby curcumin dampens inflammatory processes and restores immune homeostasis.

With a broad mechanistic profile combined with an increasing volume of preclinical and clinical data, curcumin is a promising natural candidate for therapeutic use in the treatment of chronic inflammatory and immune-related diseases. The benefits accruing in models of metabolic syndrome, arthritis, neuroinflammation, cardiovascular disorders, and certain types of cancers have emphasized the wide therapeutic scope of this agent. Though challenges persist regarding poor bioavailability, novel delivery systems, including nanoparticles, liposomes, phospholipid complexes, and structural analogs, have greatly improved its pharmacokinetic profile. This development further reinforces translational prospects for curcumin, strengthening the scientific rationale underlying its development as an adjunctive or stand-alone therapeutic agent.

Despite these promising findings, many knowledge gaps still persist that need to be filled before curcumin could be integrated into evidence-based clinical practice. Mechanistic investigations will be required to define further target specificity, dose-response relationships, and interactions in complex inflammatory and immune networks. Larger-scale, well-controlled clinical trials are needed for the transparent validation of efficacy, safety, and long-term disease outcomes. Concepts on bioavailability enhancement strategies, metabolic diversification, and gut microbiota interactions will also continue to improve our understanding of the physiological behavior and further the therapeutic potential of curcumin. Ongoing interdisciplinary investigation will strengthen not only the scientific underpinnings of curcumin-based therapeutics but also the rational development of more effective, natural-product-driven interventions for chronic inflammatory disease.

Acknowledgments

The authors are deeply grateful to the research team for their patient assistance and strong support during the progress of the study and the compilation of relevant materials. The authors also sincerely thank the two anonymous reviewers for their valuable comments and constructive suggestions during the review process, which provided important assistance in the improvement and refinement of the manuscript.

Conflict of Interest Disclosure

The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

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