Network pharmacology and plasma composition analysis of cedar pollen active compounds for treating hyperlipidemia in type 2 diabetic mice

Cedar pine pollen has long been used as both a food and therapeutic agent in traditional Chinese medicine across China and other Asian countries. Although modern research has identified various bioactive constituents in pine pollen, the hypoglycemic and hypolipidemic effects of cedar pine pollen (a specific variety) have not been systematically investigated. In this study, we established a murine model of type 2 diabetes with hyperlipidemia using a high-fat diet combined with streptozotocin. An integrated strategy incorporating in vivo pharmacodynamics, serum chemical profiling, network pharmacology, molecular docking, and UPLC-QQQ-MS/MS was adopted to elucidate the bioactivity, active substances, and mechanisms of cedar pollen. Our results showed that cedar pollen effectively reduced hyperglycemia and hyperlipidemia, enhanced endogenous antioxidant capacity, alleviated pancreatic, hepatic, and renal pathology, and restored glucose and lipid homeostasis. A total of 135 serum-absorbed compounds were identified, predominantly flavonoids, terpenoids, and phenolic acids. Network pharmacology predicted key targets (TP53, STAT3, SRC, PIK3CA) and two major pathways (PI3K-Akt and AGE-RAGE). Molecular docking confirmed stable binding between five representative monomers and core targets. Quantitative analysis determined their contents in cedar pollen: protocatechuic acid (293.46 μg/g), isoflavonic acid (117.82 μg/g), naringenin (18.06 μg/g), matairesinol (6.03 μg/g), and kaurenoic acid (0.45 μg/g). Collectively, these findings demonstrate that cedar pollen possesses reliable hypoglycemic and hypolipidemic activity, with phenolic acids, flavonoids, and terpenoids acting synergistically through a multi-component, multi-target, and multi-pathway mechanism.