Background: Conventional treatments for cancers of the head and neck region are often associated with high recurrence rates and impaired quality of life. Photodynamic therapy (PDT) has emerged as a promising alternative, leveraging photosensitizers such as hypericin to selectively target tumour cells with minimal damage to surrounding healthy tissues. Objectives: We aimed to evaluate the efficacy and underlying mechanisms of hypericin-mediated PDT (HY-PDT) in treating head and neck cancers. Methods: Adhering to PRISMA 2020 guidelines, a systematic search was conducted across PubMed/Medline, Embase, Scopus, and the Cochrane Library for studies published between January 2000 and December 2024. Inclusion criteria encompassed preclinical in vitro and in vivo studies and clinical trials focusing on HY-PDT for head and neck malignancies and its subtypes. Results: A total of 13 studies met the inclusion criteria, comprising both in vitro and in vivo investigations. HY-PDT consistently demonstrated significant cytotoxicity against squamous cell carcinoma cells through apoptotic and necrotic pathways, primarily mediated by ROS generation. Hypericin exhibited selective uptake in cancer cells over normal keratinocytes. Additionally, HY-PDT modulated the tumour microenvironment by altering cytokine profiles, such as by increasing IL-20 and sIL-6R levels, which may enhance antitumor immunity and reduce metastasis. Conclusions: HY-PDT emerges as a highly promising and minimally toxic treatment modality for head and neck cancers, demonstrating efficacy in inducing selective tumour cell death and modulating the immune microenvironment. Despite the encouraging preclinical evidence, significant methodological variability and limited clinical data necessitate further large-scale, standardized and randomized controlled trials.

Background: Oral biofilms are a major etiological factor in dental caries, periodontal disease, peri-implantitis, and endodontic infections. Increasing antimicrobial resistance and the limitations of conventional therapies have intensified interest in antimicrobial photodynamic therapy (aPDT). Hypericin, a natural photosensitizer derived from Hypericum perforatum, demonstrates potent reactive oxygen species generation and broad antimicrobial activity; however, its dental applications remain insufficiently synthesized. Objective: To systematically evaluate the antimicrobial efficacy, treatment parameters, safety, and clinical potential of hypericin-mediated aPDT against oral biofilms and infections in dentistry. Methods: This systematic review was conducted according to PRISMA 2020 and registered in PROSPERO CRD42024617727. Electronic searches of PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library (January 2010 to December 2025) were performed. Studies assessing hypericin-mediated aPDT in oral or dental contexts were included. Methodological quality was evaluated using a predefined nine-domain risk-of-bias tool. Results: Eleven studies met the inclusion criteria. Hypericin-mediated aPDT demonstrated strong antimicrobial effects, achieving up to 99% planktonic inactivation and significant biofilm reduction across bacterial and fungal species. Activity was particularly pronounced against Gram-positive organisms, including Staphylococcus aureus and Enterococcus faecalis. However, efficacy against mature biofilms was variable and often dependent on formulation and irradiation parameters. Most studies showed moderate methodological quality, with frequent deficiencies in reporting light calibration and dosimetry. Advanced delivery systems, including liposomal and nanoparticle formulations, improved photodynamic performance. Conclusions: Hypericin-mediated aPDT shows promising antimicrobial activity against oral pathogens and biofilms, with favorable selectivity and safety profiles. Nevertheless, the evidence remains predominantly preclinical and heterogeneous. Standardized protocols and well-designed clinical trials are required before routine dental implementation can be recommended.

Background: Hypericin is a natural photosensitizer with promising antifungal potential, but its uptake kinetics in Candida (C.) albicans are not well defined. Objective: To characterize the time-dependent uptake of hypericin by C. albicans in vitro using fluorescence microscopy and quantitative image analysis. Methods: C. albicans ATCC 90028 was standardized to 0.5 McFarland and incubated with hypericin dissolved in DMSO. Samples were illuminated with an LED system tuned near 550 nm and imaged using a CCD fluorescence microscope with emission recorded above ≈600 nm. Images were analyzed in ImageJ, using a control-based threshold and percentage area (the percentage of pixels above the threshold in the whole field) as a fluorescence measure. Time points were 1, 3, 5, 7, 10, 15, 20, 25, 30, 35, 40, and 45 min, plus a separate dark-only series at 35–45 min. Data from three experiments were evaluated by ANOVA. Results: Fluorescence increased rapidly and showed a nonlinear, biphasic profile under light, with local maxima around 5–7 and 15–30 min. Dark-only samples at 35–45 min had a lower %Area and lacked a clear biphasic pattern. Conclusions: Hypericin uptake by C. albicans is dynamic, nonlinear, and light-dependent. These kinetics should be considered when designing hypericin-based antifungal photodynamic therapy protocols.