Human Interleukin-1 Alpha (IL-1α) is a pro-inflammatory cytokine belonging to the IL-1 family—which includes IL-1α, IL-1β, and the IL-1 receptor antagonist (IL-1Ra)—and plays a central role in initiating innate immune and sterile inflammatory responses. Unlike IL-1β, IL-1α is constitutively expressed in epithelial, endothelial, and other barrier tissues and functions as an intracellular alarmin that is rapidly released upon cell injury, necrosis, or cellular stress. Once released, IL-1α binds to the IL-1 receptor type 1 (IL-1R1), activating NF-κB and MAPK signaling pathways that drive leukocyte recruitment, endothelial activation, fever, and amplification of downstream pro-inflammatory cytokine cascades. IL-1α is critically involved in inflammatory skin diseases, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, cancer-associated inflammation, and sterile injury responses such as ischemia–reperfusion damage. While essential for host defense and tissue repair, dysregulated or excessive IL-1α signaling contributes to chronic inflammation and tissue pathology. As both a biomarker and therapeutic target, human IL-1α is central to research on inflammasome-independent inflammation, tumor microenvironment biology, and development of IL-1–targeted biologics aimed at modulating cytokine-driven disease.