Integrated lipidomics and Chinmedomics reveal the multi-target mechanism of Phellodendri Amurensis Cortex in prostate cancer via lipid metabolism remodeling.

ETHNOPHARMACOLOGICAL RELEVANCE: Phellodendri Amurensis Cortex (PAC), a traditional Chinese medicine exhibit diverse pharmacological activities, including anticancer effects. Lipid metabolic reprogramming in the tumor microenvironment (TME) drives prostate cancer (PCa) progression and represents a promising therapeutic target; however, the effects of PAC on TME lipid metabolism remain unclear.

AIM OF THE STUDY: To investigate the anti-PCa efficacy of PAC and its underlying mechanisms by evaluating targeting lipid metabolic dysregulation in the TME.

MATERIALS AND

METHODS

A 22RV1 xenograft model was established in male BALB/c-nude mice. The therapeutic effects of PAC were evaluated using tumor growth inhibition, biochemical assays, histopathological analyses (Hematoxylin & Eosin and Oil Red O staining), TUNEL apoptosis analysis, and immunohistochemistry (Ki-67, CD31). Lipidomics was used to identify PAC-regulated lipid biomarkers and pathways. Chinmedomics and molecular docking were used to validated interactions between PAC bioactive components and core lipid-metabolizing enzymes.

RESULTS

PAC suppressed tumor growth, reduced intratumoral lipid accumulation, inhibited proliferation (Ki-67↓) and angiogenesis (CD31↓), and induced apoptosis (TUNEL↑). Thirty dysregulated lipid markers were identified in PCa, and PAC reversed 27 of them involved in glycerophospholipid, arachidonic acid, and sphingolipid metabolisms. Chinmedomics identified nine PAC components (e.g., berberine, magnoflorine) targeting phosphatidylserine synthase 1 (PTDSS1), phospholipase A and acyltransferase 3 (PLAAT3), phosphatidylethanolamine N-methyltransferase (PEMT), and phospholipase D family member 4 (PLD4), confirmed by molecular docking. These interactions disrupted phospholipid homeostasis and energy metabolism.

CONCLUSIONS

PAC exerts anti-PCa effects by reprogramming lipid metabolism via multi-component targeting of PTDSS1/PLAAT3/PEMT/PLD4, thereby inhibiting proliferation, promoting apoptosis, and remodeling the TME. This study reveals a novel lipid-centric mechanism for PCa intervention using PAC.