Functional groups as functional drivers: structure-activity relationships in humic substances for medical applications

Abstract

Humic substances (HSs) have long been used in traditional medicine, but their translation into modern therapeutics has been limited by a lack of mechanistic understanding of their structure-activity relationships. This study combines bibliometric analysis of 1860 Web of Science publications (2000-2025) with a critical review to address this gap. The inclusion of 17 articles from 2025 did not alter the overall trend analysis. Bibliometric analysis reveals a pronounced disciplinary imbalance, with Environmental Sciences dominating the literature (480/1860) compared to Pharmacology & Pharmacy (48/1860). Research focus has shifted from adsorption processes (2006-2010) to HS-based nanocarriers and photothermal therapy (2016-2025). However, despite growing interest in biomedical functionalities, only a limited number of studies have progressed to preclinical validation. The integrated critical review identifies specific functional groups in HSs as key determinants of biological activity, including: (1) carboxylic and phenolic hydroxyl groups enable pH-responsive drug delivery and chelation of heavy metals; (2) quinone moieties regulate redox homeostasis via reactive oxygen species scavenging and electron transfer modulation, underpinning anti-inflammatory, antioxidant, and antimicrobial effects; (3) amphiphilic architectures, comprising hydrophobic aromatic cores and hydrophilic groups, enhance solubility and intestinal permeability of poorly bioavailable drugs; (4) aromatic ring systems facilitate non-specific binding to enzymes and signaling proteins, inhibiting pro-tumorigenic pathways and attenuating inflammatory cascades. Methodological limitations include reliance on a single database and inconsistent HS characterization. Future research should prioritize standardized HS purification, clinical trials of HS-based formulations, and concerted interdisciplinary effort to bridge the gaps between structural characterization and translational applications.

Keywords: Bibliometrics; Fulvic acids; Humic acids; Humic substances; Hydrogel; Sodium humate.