The manipulation of the cedrol metabolism pathway by baricitinib and its immune interaction mechanism against chemotherapy-induced alopecia.

Cedrol (CE), a bioactive component derived from ginger, has demonstrated a favorable anti-chemical-induced alopecia (CIA) effect, yet the combined therapeutic efficacy and underlying mechanism of CE with baricitinib (BT) remain unreported. This study was designed to explore the key synergistic mechanism through which the co-administration of CE and BT (CE + BT) alleviates cyclophosphamide (CP)-induced immunosuppression and exerts therapeutic effects against CIA. The anti-CIA activity of CE + BT was validated in a CP-induced CIA mouse model; to elucidate the potential synergistic mechanism of CE + BT, molecular docking and molecular dynamics simulations were performed in combination, and additionally, analytical techniques including GC-MS, LC-MS, and HPLC, as well as biological approaches such as qRT-PCR, enzyme inhibition assays, siRNA-mediated interference, cellular thermal shift assay, and mouse imaging, were employed to investigate the synergistic interactions and metabolic crosstalk between CE and BT. The results showed that CE + BT could effectively promote hair regrowth and ameliorate immunosuppression in CIA mice; network pharmacology analysis revealed that CE + BT mediates its synergistic anti-CIA effect via the PTGS2/CDK4 signaling pathway, which was further verified by multi-dimensional experiments; metabolic pathway analysis indicated that when combined with BT, CE + BT could inhibit the formation of CE epoxide and ring-opening metabolites, slow down the in vivo and in vitro metabolism of CE (with no impact on BT metabolism), and enhance the cutaneous retention of CE. CE + BT can alleviate hair loss in CIA mice, and the PTGS2/CDK4 pathway has been identified as the key pathway responsible for its synergistic therapeutic effects, providing novel alternative treatment strategies and insights for the precision clinical application of BT.