Using an Unbiased Coexpression Network to Reveal Cross‐Talking Pathways of Phosphoinositide‐3‐Kinase Regulatory Subunit 1 in Skin Aging and Rejuvenation

Skin aging is a highly complex process embracing chronological aging and photoaging. Continuous advancement in the study of skin aging facilitates the innovations of skin rejuvenation therapies. However, the mechanism underlying skin aging remains largely unexplored. Herein, differential expression gene (DEG) analysis identified a gradual down-regulation of PIK3R1 in aged untreated skin, aged treated skin (treated with intense pulsed light), and young skin. Among 11 964 background genes, thousands of DEGs were identified in all aged/young and PIK3R1-low/high groups. Coexpression modules were created using weight gene correlation network analysis, showing an enrichment in PI3K/AKT, Rap1, regulating pluripotency of stem cells (rPSC), etc. Furthermore, DEGs with strong relation to skin vitality and PIK3R1 were extracted for network analysis, wherein cross-talking pathways of PIK3R1 including PI3K/AKT, Rap1, and rPSC were identified. The same cross-talking pathways were also replicated in aged untreated and treated skin, as implemented by enrichment analyses of DEGs in aged untreated versus young or aged treated skin. According to the area under the curve of 100% and 88%, PIK3R1 possibly predicted skin aging and skin rejuvenation, respectively. RT-PCR and western blot confirmed the decline of PIK3R1 expression in aged treated and young skin, compared with aged untreated skin. PIK3R1 knockdown led to increased p-AKT (Ser473) and Bcl-2, and decreased p-FOXO1 (Ser256) and MMP-1, which may be the cause of more resistance to ultraviolet A induced cell senescence, proliferation inhibition, apoptosis, and collagen synthesis decline in PIK3R1 knockdown HDFs. Our study preliminarily elucidates the comprehensive role of PIK3R1 in skin aging, providing a potential new target for skin rejuvenation.