A cell-free browning strategy: Exosomal miR-21a-5p from ADSCs targets PDCD4 to reshape adipose metabolism.

Adipose-derived stem cell exosomes (ADSC-EXOs) serve as cell-free therapy, transporting signaling molecules that modulate adipose plasticity. However, the precise molecular mechanisms involved remain unclear. We used a high-fat diet-induced mouse obesity model and an MDI-induced 3T3-L1 cell differentiation model. We found that ADSC-EXOs improved systemic glucose and lipid metabolism, decreased PDCD4 and white adipocyte marker expression, and increased brown adipocyte marker expression along with the activation of the LXR-α/Akt pathway in inguinal adipose tissue. miR-21a-5p mimic or siPDCD4 transfection in 3T3-L1 cells recapitulated these effects, reducing lipid accumulation and promoting adipocyte browning, whereas PDCD4 overexpression produced the opposite effects. Mechanistically, miR-21a-5p directly targeted the 3' UTR of PDCD4. These findings indicate that ADSC-EXOs facilitate white fat browning through the miR-21a-5p/PDCD4 axis and thus activate the LXR-α/Akt signaling pathway, offering a potential therapeutic strategy for obesity-related metabolic dysfunction.