PLEKHO1 (also known as CKIP-1) is a multifunctional scaffold protein that regulates diverse cellular processes through interactions with multiple proteins including CK2α, ATM, Akt, and Smurf1 1. The protein functions as a negative regulator of bone formation by promoting Smurf1-mediated ubiquitination and degradation of Smad1/5, thereby suppressing BMP signaling in osteoblasts 2. PLEKHO1 expression increases with aging and contributes to age-related bone loss 2. In inflammatory conditions, PLEKHO1 exacerbates joint inflammation in rheumatoid arthritis by facilitating TRAF2-mediated RIP1 ubiquitination to activate NF-κB signaling in osteoblasts 3. The protein also negatively regulates cementoblast mineralization through modulation of p38, Akt, and MAPK pathways 4. Notably, PLEKHO1 exhibits tumor-promoting activity in renal cell carcinoma, where its knockdown inhibits cell viability through Hippo and MAPK/JNK pathways 5. The 3'UTR of PLEKHO1 has cardioprotective functions, activating CaMKK2/AMPK/cTNI signaling to protect against sleep deprivation-induced cardiac dysfunction 6. These diverse functions make PLEKHO1 a potential therapeutic target for bone diseases, inflammatory conditions, and cancer.