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Adult mammals are incapable of multitissue regeneration, and augmentation of this potential may shift current therapeutic paradigms. We found that a common co-receptor of interleukin 6 (IL-6) cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) were resistant to surgically induced osteoarthritis as reflected by reduced loss of proteoglycans, reduced synovitis, and synovial fibrosis. The F814 mice also exhibited enhanced regenerative, not reparative, responses after wounding in the skin. In addition, pharmacological modulation of gp130 Y814 upstream of the SRC and MAPK circuit by a small molecule, R805, elicited a protective effect on tissues after injury. Topical administration of R805 on mouse skin wounds resulted in enhanced hair follicle neogenesis and dermal regeneration. Intra-articular administration of R805 to rats after medial meniscal tear and to canines after arthroscopic meniscal release markedly mitigated the appearance of osteoarthritis. Single-cell sequencing data demonstrated that genetic and pharmacological modulation of Y814 resulted in attenuation of inflammatory gene signature as visualized by the anti-inflammatory macrophage and nonpathological fibroblast subpopulations in the skin and joint tissue after injury. Together, our study characterized a molecular mechanism that, if manipulated, enhances the intrinsic regenerative capacity of tissues through suppression of a proinflammatory milieu and prevents pathological outcomes in injury and disease. Reinvigorating tissue regeneration: Enhancing the regenerative capacity of adult tissues could improve wound healing and resistance to chronic degenerative diseases. Here Shkhyan and colleagues identified a tyrosine residue at position 814 (Y814) of glycoprotein 130 (gp130) that functioned as a cellular stress sensor responsible for inflammatory responses. By replacing the tyrosine with a phenylalanine (F814), the authors were able to achieve downregulation of pro-inflammatory and pro-fibrotic signaling cascades after stimulation in vitro. F814 mice demonstrated increased resistance to development of osteoarthritis and enhanced skin regeneration after wounding, and a small molecule that modulated gp130 receptor pro-inflammatory signaling also improved symptoms of osteoarthritis in rodents and dogs. These findings suggest that targeting Y814 in gp130 may potentially improve tissue regeneration. —MN [ABSTRACT FROM AUTHOR]