Background/Objectives: The global health functional food (HFF) market is expanding rapidly, driven by increasing consumer interest in preventive healthcare and evidence-based nutrition. The Republic of Korea has established a systematic regulatory framework for HFFs, through the Individually Recognized Functional Ingredient (IRFI) system introduced in 2004. Designed to accommodate innovative physiologically active ingredients beyond standardized categories, the IRFI system is increasingly discussed as a regulatory model for evidence-based functional foods. This study examines the IRFI system within a comparative regulatory context and evaluates its implications for drug–dietary supplement interactions (DDSIs). Methods: Functional categories were defined according to guidelines issued by the Ministry of Food and Drug Safety (MFDS). Data on Korean IRFIs were obtained from the Food Safety Korea database. A literature search was conducted in PubMed using regulatory keywords which identified through Google searches. Regulatory frameworks in the United States, European Union, Japan, and China were comparatively analyzed. DDSIs were reviewed based on MFDS-approved IRFIs and the relevant literature. Results: The IRFI represents a hybrid regulatory model that combines rigorous pre-market scientific evaluation, including GLP-compliant safety testing and human clinical evidence, with regulatory incentives such as expedited review and temporary market exclusivity. Compared with post-market-oriented systems in the United States and Japan, the stringent authorization framework in the European Union, and the dual-track health food system in Chinese, IRFI integrates clinical evidence requirements within a structured pre-market approval process. Conclusions: The IRFI framework establishes a comparatively stringent evidentiary standard for functional foods while providing a structured basis for evaluating potential DDSIs. Its applicability depends on alignment and mutual recognition of scientific and clinical evaluation criteria across regulatory jurisdictions. DDSIs were reviewed based on MFDS-approved IRFIs and the relevant literature.

Hyun Hwan Hwang, Ki Ho Chang, Yi Young Choi, Ii-Du Jung, In-Cheol Kang, Youngjin Choi, Mi Jin O, Chang-Keun Cho, Pureum Kang, Hye-Jung Park, Choon-Gon Jang, Seok-Yong Lee. DTT 2022;1:1-11. https://doi.org/10.58502/DTT.22.003

Background and aim: Statins increase hepatic low‐density lipoprotein receptor (LDLR) expression but also induce proprotein convertase subtilisin/kexin type 9 (PCSK9), which promotes LDLR degradation and may limit the lipid‐lowering response. Although betulinic acid (BA) has been reported to reduce basal PCSK9 expression, whether it counteracts the compensatory increase in PCSK9 during statin treatment remains unclear. We investigated the effect of BA on atorvastatin‐induced PCSK9 upregulation and the contribution of farnesoid X receptor (FXR)/small heterodimer partner (SHP) signaling. Experimental procedure: The effects of BA were examined in HepG2 and Huh7 cells using ELISA, RT‐qPCR, and immunoblotting. RNA sequencing, pharmacological modulation of FXR, siRNA‐mediated knockdown of FXR or SHP, time‐course analysis, and co‐immunoprecipitation were used to investigate the underlying mechanism. The effects of BA alone or combined with atorvastatin were also evaluated in high‐fat diet‐fed mice. Key results: BA reduced basal and atorvastatin‐induced PCSK9 expression and secretion while maintaining or increasing LDLR expression in both cell lines. BA increased SHP and SLC51B expression and reduced CYP7A1 and CYP8B1 expression. Pharmacological modulation and siRNA‐mediated knockdown showed that reduced FXR or SHP expression weakened BA‐mediated regulation of PCSK9 and LDLR. BA also increased the SHP signal detected in SREBP2 immunoprecipitates without a marked reduction in SREBP2 abundance. In high‐fat diet‐fed mice, BA reduced circulating and hepatic PCSK9 and further lowered serum LDL‐c during atorvastatin treatment. Conclusions and implications: This study extends the known PCSK9‐lowering activity of BA by showing that BA counteracts statin‐induced PCSK9 upregulation through an FXR/SHP‐associated mechanism. These findings support BA as a potential modulator of the PCSK9–LDLR axis during statin treatment.