Abstract
Kalanchoe blossfeldiana, a medicinal succulent known for rich phytochemical diversity, hasn't been extensively explored for lipid-lowering potential. Given growing burden of hyperlipidemia and limitations of current therapies, novel natural alternatives with multi-target synergistic mechanisms are of increasing interest. This study aimed to investigate antihyperlipidemic activity of K. blossfeldiana leaf extracts and its bioactive compounds through multidisciplinary approach. Sequential extractions were performed using solvents of increasing polarity. Phytochemical estimation revealed that ethanolic cold extract obtained via ultrasonic-assisted cold extraction exhibited highest phenolic (102.46 ± 2.05 µg/mL) and flavonoid (86.88 ± 1.29 µg/mL) content, LC-MS/MS-QQQ analysis identified 61 phytocompounds, including kaempferol-3-O-rutinoside, kaempferol-3-O-glucuronide, quercetin-3,4'-di-O-glucoside, quercetin-3-O-rutinoside, and apigenin-7-O-glucoside. Ethanolic cold extract showed potent pancreatic lipase inhibition via fluorometric assay (IC(50) = 23.33 µg/mL) comparable to standard orlistat and significantly improved lipid profiles in cholesterol-fed female albino rats, reducing cholesterol, triglycerides, LDL-C, and VLDL-C while increasing HDL-C (P < 0.005) comparable to standard atorvastatin. Molecular docking revealed strong binding affinities, particularly for quercetin-3-O-rutinoside against HMG-CoA reductase (- 9.023 kcal/mol) and quercetin-3,4'-di-O-glucoside against pancreatic lipase-colipase (- 9.139 kcal/mol). Molecular Dynamic simulations over 100 ns confirmed stability of these complexes with minimal RMSD and RMSF fluctuations. In silico ADMET profiling indicated favorable pharmacokinetic and toxicity profiles for both compounds (LD(50) 5000 mg/kg). Multidisciplinary evidence supports the ethanolic cold extract of K.blossfeldiana as promising antihyperlipidemic agent. Quercetin-based derivatives were identified as key bioactives, meriting further investigation for isolation and development as lead compounds. Further pharmacokinetic, toxicity, and efficacy studies are necessary for clinical translation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00560-4.