Sexual dimorphism is a fundamental characteristic of various physiological and pathological processes in humans, including immune responses, senescence, and metabolism. Most studies on the sex bias have focused on sex hormones or female-biased genes, whereas male-biased genetic factors remain understudied. Here, we show that the Y-linked noncoding RNA, RP11-424G14.1, is expressed in human male keratinocytes. Microarray study suggests the NF-κB pathway as the top biological pathway affected by RP11-424G14.1 knockdown, consistent with known sex differences in inflammation. Additionally, IGFBP3 is identified as the top gene supported by RP11-424G14.1 in male keratinocytes. Conversely, in female keratinocytes, IGFBP3 is the top gene repressed by the X-linked long noncoding RNA XIST, suggesting a central role of IGFBP3 in mediating sexual dimorphism. Knockdown of RP11-424G14.1 or IGFBP3 in male keratinocytes inhibits cellular senescence, consistent with increased longevity in females. IGFBP3 expression is dependent on insulin, and metabolomics analysis suggests that RP11-424G14.1 and IGFBP3 regulate acrylcarnitine metabolism. Our study identifies the role of the RP11-424G14.1-IGFBP3 pathway in coordinating sex differences in immunity, senescence, and metabolism. With RP11-424G14.1 being a human-specific genetic element, our study suggests the evolving feature of sexual dimorphisms in biological processes.