Skin cancer presents a significant global health burden with rising incidence. The side effects of current therapies and the emergence of drug resistance necessitate the exploration of alternative and complementary strategies. Natural products, with their long history of use in treating skin disorders, have emerged as a promising source of novel therapeutic agents. This review comprehensively elucidates the potential efficacy of natural bioactive compounds in both preventing and treating skin cancer. We summarize the molecular mechanisms through which key natural bioactive compounds exert their anti-skin cancer effects, including induction of apoptosis, inhibition of proliferation and metastasis, anti-inflammatory and antioxidant activities, DNA damage repair, and photoprotection. Furthermore, we discuss the biological barriers relevant to skin cancer therapy using natural bioactive compounds and link them to corresponding delivery strategies, while identifying key translational challenges. In conclusion, natural bioactive compounds offer a multi-targeted and synergistic approach against skin carcinogenesis, holding substantial promise as sources of adjuvant therapies and chemopreventive agents to improve patient outcomes.

Cutaneous squamous cell carcinoma (cSCC) is a common malignant skin tumor with invasive potential and risk of recurrence. This study investigated the anti-cSCC effects of luteolin in vitro and in vivo and explored the associated molecular mechanisms. The effects of luteolin on A431 cell viability were assessed by CCK-8 assay, and apoptosis was analyzed by Annexin V-FITC/propidium iodide (PI) double staining. qRT-PCR and Western blot analyses were performed to evaluate apoptosis-related factors and the EGFR/PI3K/AKT signaling pathway. Molecular docking was further conducted to explore the potential interactions of luteolin with EGFR/PI3K/AKT signaling-related proteins and apoptosis-associated proteins. In vivo, a two-stage skin carcinogenesis model induced by 7,12-dimethylbenz[a]anthracene (DMBA) and croton oil was used to evaluate the antitumor activity of luteolin. Luteolin significantly inhibited A431 cell viability and promoted apoptosis in a concentration-dependent manner. Moreover, luteolin increased Bax expression and decreased Bcl-2 expression at both the mRNA and protein levels. Mechanistically, luteolin suppressed the phosphorylation of EGFR, PI3K, and AKT. Molecular docking suggested that luteolin could interact with EGFR, PIK3CA, AKT, Bax, and Bcl-2, providing supportive in silico evidence for its potential modulation of EGFR/PI3K/AKT signaling and apoptosis-related proteins. In vivo, luteolin alleviated body weight loss, achieved a tumor nodule inhibition rate of 45.28%, significantly improved spleen and thymus indices (p < 0.05), and ameliorated histopathological damage in skin tissues. In addition, immunohistochemical analysis showed that luteolin reduced Ki-67 expression. These results indicate that luteolin exerts anti-cSCC effects in vitro and in vivo, possibly through modulation of the EGFR/PI3K/AKT signaling pathway and apoptosis-related proteins.

Sanghuangporus sanghuang (Sanghuang) extract, obtained from the medicinal and edible fungus Sanghuang, was examined for its inhibitory effects against Candida albicans and its potential role in mitigating intestinal inflammation related to ulcerative colitis (UC). Its anti-Candida albicans activity was assessed by measuring the minimum inhibitory concentration (MIC), evaluating its ability to suppress biofilm formation, and observing fungal morphological changes using scanning electron microscopy (SEM). Using mice with dextran sulfate sodium (DSS)-induced UC and intestinal Candida albicans (C. albicans) colonization, fungal burden, intestinal inflammation, mucosal injury, intestinal bacterial community composition, and related signaling pathways were assessed. Sanghuang extract inhibited C. albicans growth and suppressed biofilm formation. SEM further revealed reduced hyphal development and disruption of cell surface morphology following treatment. In vivo, Sanghuang administration ameliorated UC-related phenotypes, with descriptive decreasing trends in fecal C. albicans burden, less severe colonic injury, and lower colonic levels of IL-6, IL-1β, and TNF-α, accompanied by changes in intestinal bacterial community composition. Network pharmacology analysis suggested that pathways associated with phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) may participate in this process. Molecular docking yielded predicted interactions of caffeic acid with PTGS2, EGFR, PIK3CA, AKT1, and mTOR. qRT-PCR further showed that Sanghuang extract reduced the colonic mRNA expression of Pik3ca, Akt1, and Mtor. These findings provide experimental evidence that Sanghuang extract exerts antifungal activity in vitro and is associated with changes in fecal C. albicans burden and colitis-associated inflammatory responses in this mouse model.

Endophytic fungi form complex symbiotic associations with medicinal plants via long-term coevolution. Such cross-kingdom interactions substantially modulate flavonoid biosynthesis in host plants. This review dissects the mechanisms through which endophytic fungi elevate flavonoid accumulation in medicinal plants. We first summarize symbiotic and growth-promoting relationships between endophytic fungi and medicinal plants, outlining four core synergistic functions: nutrient supply, phytohormone homeostasis, stress resistance enhancement, and secondary metabolism activation. We then elaborate on three primary regulatory patterns underlying endophyte-modulated flavonoid biosynthesis, including direct activation of plant flavonoid biosynthetic pathways, indirect regulation via stress mitigation and host metabolic reprogramming, and autonomous flavonoid production by endophytic fungi. Notably, most current evidence for autonomous flavonoid biosynthesis by endophytic fungi is derived from axenic cultures, whereas its occurrence and quantitative contribution within colonized plant tissues remain to be established. We further discuss state-of-the-art technologies for untangling plant–fungus symbiotic interactions, including multi-omics integration, spatial metabolomics, single-cell sequencing, synthetic microbial consortia, and CRISPR-Cas genome editing. Lastly, we propose future research perspectives covering green cultivation of medicinal plants, targeted improvement of medicinal quality, and efficient microbial biosynthesis of flavonoids.