These findings uncover a critical role of mechano-controlled inflammation in the cell fate decision of BMMSCs and raise the possibility of targeting the Piezo1-c-Jun-Ccl2-NF-κB-Lcn2 axis as a promising strategy for the development of BMMSC-based therapies for aging- and obesity-related chronic disorders. Here, NFKB1 is linked to obesity due to melanocortin 4 receptor deficiency.