Melasma: Pathogenesis, Therapeutic Limitations, and the Emerging Potential of Metformin and Propolis as a Multi-Target Topical Strategy- A Narrative Review

Melasma is a chronic, relapsing disorder of hyperpigmentation that predominantly affects women of reproductive age, particularly those with darker skin phototypes in regions of high ultraviolet (UV) exposure. Despite its benign nature, melasma exerts a profound psychosocial burden, significantly impairing quality of life. Current therapeutic modalities—including topical hydroquinone, triple combination creams, chemical peels, and laser therapies—remain inadequate due to limited efficacy, high recurrence rates, safety concerns with long-term use, and failure to address the multifactorial pathogenesis of the disease. This narrative review comprehensively examines the pathophysiology of melasma, the molecular mechanisms underpinning melanogenesis, current treatment approaches and their limitations, and the scientific basis for a novel multi-target therapeutic strategy combining metformin hydrochloride and propolis extract. Metformin inhibits upstream melanogenesis signaling through AMPK activation, cAMP reduction, and MITF downregulation, while propolis—a lipophilic resinous bee product rich in flavonoids and polyphenols—exerts direct tyrosinase inhibition alongside antioxidant and anti-inflammatory activities. Together, these agents offer complementary, multi-level inhibition of the melanogenic pathway. The emulgel delivery platform is discussed as a rational co-delivery system capable of simultaneously accommodating both the hydrophilic metformin and the lipophilic propolis extract. This review highlights the scientific and clinical rationale for this innovative combination and identifies key directions for future preclinical and clinical development.