Optimal dose window, formulation efficacy, and molecular mechanisms of curcumin in MASLD animal models: A systematic review and three-level meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Approximately 25% of the global adult population is affected by metabolic dysfunction-associated steatotic liver disease (MASLD), yet no universally approved first-line pharmacotherapy exists. Curcumin is the major bioactive constituent of turmeric (Curcuma longa L.), a plant with a long history of use in traditional medicine systems for treating digestive, inflammatory, and liver disorders. Despite promising multi-targeted activity, the clinical application of curcumin is hindered by poor bioavailability and inconsistent efficacy due to variable dosing and formulations.

AIM OF THE STUDY: This systematic review and meta-analysis aimed to: (1) identify the optimal dose range of curcumin for MASLD intervention in preclinical models; (2) quantitatively compare the efficacy of different curcumin-based formulations; and (3) validate its modulation of key mechanistic targets including SREBP-1c, PPARα, TNF-α, and Nrf2.

MATERIALS AND

METHODS

PubMed, Embase, and Web of Science were searched from inception to December 2025 for in vivo studies evaluating curcumin interventions in mouse or rat models of MASLD. A three-level meta-analysis with robust variance estimation (RVE) was used to handle data dependencies from multi-dose studies. The study protocol was preregistered with PROSPERO (CRD420261276896). Non-linear dose-response relationships were modeled using restricted cubic splines (RCS). Efficacy differences across formulation types were quantitatively compared, and effect sizes for key mechanistic targets were calculated.

RESULTS

Seventy-two studies were included. Dose-response analysis revealed a non-linear effect on serum ALT reduction, with an optimal window of 50-150 mg/kg; efficacy declined notably at doses >400 mg/kg. Subgroup analyses showed that curcumin derivatives and novel delivery systems were significantly more effective than native curcumin (P < 0.05). Mechanistically, curcumin significantly downregulated SREBP-1c (g = -8.00) and TNF-α (g = -4.36), and upregulated Nrf2 (g = 8.95). Following the FDA body surface area conversion, the 50-150 mg/kg animal dose corresponds to 486-1458 mg/day in humans, which is consistent with dosages used in current clinical trials. This alignment supports the biological plausibility of the animal-derived dose window, though direct translation to human dosing requires clinical validation.

CONCLUSIONS

This is the first meta-analysis to quantitatively define an optimal dose window for curcumin in MASLD animal models and to demonstrate non-linear dose-response characteristics across different formulations. Our findings provide a pharmacological rationale for dose selection in future preclinical standardization and hypothesis-driven clinical trial design for curcumin-based interventions in MASLD.