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An inflammatory microenvironment may cause organ degenerative diseases and malignant tumors. However, the precise mechanisms of inflammation‐induced diseases are not fully understood. Here, we show that the proinflammatory cytokines interferon‐γ (IFN‐γ) and tumor necrosis factor α (TNF‐α) synergistically impair self‐renewal and differentiation of mesenchymal stem cells (MSCs) via nuclear factor κB (NFκB)‐mediated activation of mothers against decapentaplegic homolog 7 (SMAD7) in ovariectomized (OVX) mice. More interestingly, a long‐term elevated levels of IFN‐γ and TNF‐α result in significantly increased susceptibility to malignant transformation in MSCs through NFκB‐mediated upregulation of the oncogenes  c‐Fos  and  c‐Myc . Depletion of either IFN‐γ or TNF‐α in OVX mice abolishes MSC impairment and the tendency toward malignant transformation with no NFκB‐mediated oncogene activation. Systemic administration of aspirin, which significantly reduces the levels of IFN‐γ and TNF‐α, results in blockage of MSC deficiency and tumorigenesis by inhibition of NFκB/SMAD7 and NFκB/c‐FOS and c‐MYC pathways in OVX mice. In summary, this study reveals that inflammation factors, such as IFN‐γ and TNF‐α, synergistically induce MSC deficiency via NFκB/SMAD7 signaling and tumorigenesis via NFκB‐mediated oncogene activation. S TEM  C ells  2013;31:1383–1395

IFN‐γ and TNF‐α Synergistically Induce Mesenchymal Stem Cell Impairment and Tumorigenesis via NFκB Signaling