Phospholipase C‐Delta1 Deletion Impairs Dermal Papilla Cell Function by Disrupting the <scp>HIF</scp> ‐1/ <scp>MAPK</scp> Signaling Pathway

ABSTRACT Phospholipase c‐delta 1 (PLCD1), a key effector in the phospholipid signaling pathway, is indispensable for the growth and development of hair follicles (HF), but its regulatory mechanism in dermal papilla cells (DPCs), the core functional cells of HF, remains unclear. In this study, a PLCD1 knockout rabbit DPC in vitro model (PLCD1 −/− ) was successfully constructed using CRISPR/Cas9 gene editing. PLCD1 knockout led to notable impairment of DPC physiological functions. Moreover, through transcriptome and metabolomics analyses, we examined differences in gene and metabolite profiles of DPCs between PLCD1 −/− and wild‐type (WT) groups, and performed an integrated association analysis of all differentially expressed genes (DEGs) and differential metabolites (DMs). The results showed widespread and significant positive and negative correlations between the screened DEGs and DMs, revealing a closely coordinated regulatory network between the transcriptome and metabolome at the global level after PLCD1 knockout. The functional status of the Hypoxia inducible factor‐1 (HIF‐1) and Mitogen activated protein kinase (MAPK) signaling pathways was further analyzed by Western blotting. The results showed that PLCD1 deficiency significantly affected the expression levels and phosphorylation status of key proteins in these two pathways. In summary, this study confirmed that PLCD1 deficiency impairs DPC function by inhibiting the HIF‐1/MAPK signaling pathway, and the mechanism depends on the PLCD1‐regulated gene–metabolite interaction network. This study provides an important theoretical basis for analyzing the regulatory mechanisms of HF growth and development and clarifies that PLCD1 and its downstream gene–metabolic network may serve as potential therapeutic targets for hair‐related diseases.