Cortex Phellodendri total alkaloids ameliorate ulcerative colitis by restoring intestinal barrier integrity via...

Cortex Phellodendri (Huangbai), the dried bark of Phellodendron chinense C.K.Schneid. (Rutaceae), represents a classic botanical drug in Traditional Chinese Medicine (TCM) historically prescribed to "clear heat and dry dampness" for treating gastrointestinal inflammatory conditions such as dysentery. However, its multi-component cooperative mechanisms remain largely enigmatic.

This study aimed to elucidate the material basis of Cortex Phellodendri total alkaloids (CPA) and investigate its systemic mechanisms and cooperative interactions in ameliorating ulcerative colitis (UC), with a specific focus on the endoplasmic reticulum (ER)-mitochondria axis.

The chemical profile of CPA was characterized using UPLC-MS/MS. In vivo efficacy and synergistic effects were evaluated in a dextran sulfate sodium (DSS)-induced colitis mouse model. The underlying molecular mechanisms were explored using DIA-based quantitative proteomics and validated via Western blotting in both colon tissues and a DSS-induced Caco-2 cellular model.

CPA effectively ameliorated DSS-induced colitis and restored intestinal barrier integrity. Proteomic and molecular validations revealed that CPA's efficacy centers on recalibrating the ER-mitochondria axis by blunting the PKR-eIF2α-ATF4 stress cascade and rescuing mitochondrial fitness through SIRT1/3 and OPA1 upregulation. Furthermore, by utilizing its two primary pure alkaloids, berberine (BBR) and phellodendrine (PHE), as mechanistic comparators, we demonstrated that the whole CPA extract exhibits robust cooperative potentiation in silencing IKK/NF-κB signaling and upregulating Claudin-1, along with potent additive effects in suppressing organelle-specific stress.

CPA serves as a scientifically validated, multi-target botanical therapeutic for the management of UC. The demonstrated BBR-PHE synergy provides a modern pharmacological blueprint for the traditional "Principal-Adjuvant" theory, highlighting the essential role of the coupled ER-mitochondria network in intestinal barrier restoration.