Interaction mechanism of low molecular weight fucoidan in targeting SR-A to modulate the MAPK signal pathway for the inhibition of oral leukoplakia.

Oral leukoplakia (OLK) is the most prevalent oral precancerous lesion, with its occurrence and progression linked to local irritants and systemic factors. Among these, chronic inflammatory microenvironment significantly promotes OLK. Conventional drug treatments have notable limitations and a high recurrence risk, underscoring the urgent need to identify reliable molecular markers and to develop effective, safe targeted therapies for OLK. This study identified abnormal overexpression of scavenger receptor A (SR-A) in the oral mucosal epithelium of patients with OLK, and low molecular weight fucoidan (LMWF) induces apoptosis in human oral precancerous lesion cells (dysplastic oral keratinocyte [DOK]) and inhibits their growth and activity. Further analyses confirmed that LMWF binds to SR-A with a binding energy of -4.4 kcal/mol through non-covalent interactions, forming a thermally stable structure. In vivo experiments showed that LMWF alleviates the pathological severity of OLK in rat models of OLK by targeting SR-A. Immunohistochemical staining showed that interleukin-1 (IL-1), transforming growth factor beta (TGF-β), protein kinase B (AKT), and Fos proto-oncogene (FOS) levels were higher in the model group; LMWF can still inhibit the expression of inflammatory cytokines to a certain extent after SR-A knockdown. Additionally, LMWF modulated IL-1, TGF-β, JUN, and FOS, thereby affecting the MAPK signaling pathway. Major histocompatibility complex class II (MHC-II) was identified as the downstream target of LMWF binding to SR-A. In summary, LMWF inhibits OLK progression by targeting SR-A to modulate the MAPK/MHC-II signaling axis and the associated genes, offering a new theoretical foundation for the development of targeted therapies for OLK.