Lian LiRuitong DongShibu FengYan Huang0000-0001-8043-704XLiew Ping XinHanyun QueHuan LiPeng WangLeu Kim FeyYi ZhangZhaotong CongSanyin Zhang2026-10-202026-10-202026-03-2710.3390/ijms27073073https://dspace-cris.utar.edu.my/handle/123456789/11800Bitter compounds may function not only as taste substances but also as important active constituents mediating therapeutic effects. Their recognition is primarily mediated by bitter taste receptors (TAS2Rs), which exert pharmacological effects, such as regulating glucose metabolism, anti-inflammatory properties, and immune modulation, aligning closely with the therapeutic effects of bitter Chinese herbal medicine (BCHM). Contemporary pharmacological research has increasingly underscored the therapeutic potential of bitter traditional Chinese medicine (TCM), particularly through their bioactive constituents in the prevention and treatment of diverse pathological conditions. Here, we systematically review the diversity of bitter compounds from TCM and features of TAS2Rs, including their tissue distribution, physiological functions, structural characteristics, signal transduction mechanisms, and single-nucleotide polymorphisms. While numerous bitter phytochemicals have been characterized as agonists of TAS2Rs, the precise physiological functions and underlying molecular mechanisms mediated by TAS2R activation remain incompletely elucidated. This knowledge gap is largely attributable to several methodological and biological challenges, including the widespread tissue distribution of TAS2Rs, the complexity of their downstream signaling cascades, and the structural and functional heterogeneity of bitter compounds. This review outlines theoretical foundations, future perspectives and challenges for the drug development of TAS2R from BCHM. © 2026 by the authors.en-USbitter taste receptorsChinese herbal medicinepharmacological effectssignaling pathwayAnimalsDrugsChinese HerbalHumansLigandsMedicineChinese TraditionalPhytochemicalsReceptorsG-Protein-CoupledSignal TransductionTasteTaste ReceptorsType 2baicalinberberinecoptisineflufenamic acidG protein coupled receptorherbaceous agentlimoninphellodendrinetaste 2 receptorunclassified drugligandphytochemicaltaste receptor type 2antiinflammatory activityantineoplastic activitybitter tasteblood vessel tonebronchodilatationcardiovascular systemChinese medicineconformational transitiondigestive systemgenetic variationglucose metabolismhumanimmune systemimmunomodulationligand bindingnervous systemnonhumanrespiratory systemReviewsignal transductionsingle nucleotide polymorphismsmooth muscle relaxationsystematic reviewtissue distributionurogenital systemanimalchemistrydrug effectgeneticsmetabolismprocedurestastetext::journal::journal article::review article