<![CDATA[Melasma is a chronic, relapsing facial hypermelanosis sustained by photic exposure, melanocyte hyperactivity, inflammation, oxidative stress, vascular signaling, and dermal remodeling. Interest in non-hydroquinone therapies has increased because irritation and recurrence often limit long-term care. Objective to systematically evaluate the efficacy, safety, formulation characteristics, and mechanistic PubMed/MEDLINE, Scopus, Web of Science, Embase, CENTRAL, ScienceDirect, ClinicalTrials.gov, and WHO ICTRP were searched from database inception to 19 July 2026. The included studies were published between 2012 and 2025. The search identified 455 records; after duplicate removal and screening, 35 full-text reports were assessed for eligibility and 12 studies were included in the qualitative synthesis. Randomized and non-randomized clinical studies evaluating the eligible active ingredients as monotherapy or interpretable combinations were included. Risk of bias was assessed using RoB 2, ROBINS-I, or Joanna Briggs Institute tools, and certainty of evidence was evaluated using GRADE. Clinical and formulation heterogeneity precluded meta-analysis; therefore, structured narrative synthesis and evidence mapping were performed. Twelve studies met the eligibility criteria and were included in the qualitative synthesis. Seven evaluated topical tranexamic acid, three assessed alpha-arbutin-containing interventions, and two investigated hexylresorcinol-containing formulations. Nine studies directly enrolled patients with clinically diagnosed melasma, one included a mixed population of women with melasma or facial dark spots, and two provided indirect evidence from general facial or body hyperpigmentation. Topical tranexamic acid, generally administered at concentrations of 3–5% for 8–12 weeks, showed the most consistent reductions in MASI or mMASI and frequently produced short-term responses that were not significantly different from those obtained with hydroquinone, while generally causing fewer local irritant reactions. Alpha-arbutin-containing regimens improved pigmentation, but most involved co-active ingredients or enhanced-delivery systems. Hexylresorcinol reduced pigmentation in randomized dyspigmentation studies, although melasma-specific evidence remained limited. No factorial trial demonstrated clinical synergy among the three agents. Topical tranexamic acid has the strongest, although low-certainty, evidence. Alpha-arbutin and hexylresorcinol are promising, but ingredient-specific efficacy, durability, and synergy remain unconfirmed.]]>
