Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults. However

a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60. Elderly patients with osteosarcoma exhibit different characteristics compared to young patients

which usually results in a poor prognosis. The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications. Senescent cells can accelerate tumor progression by metabolic reprogramming. Recent research has shown that methylmalonic acid (MMA) was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics. We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells. The expression of

MAFB

was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged. Specifically

we first confirmed a novel molecular mechanism between cellular senescence and cancer

in which the MMA-driven transcriptional reprogramming of the

MAFB-NOTCH3

axis accelerated osteosarcoma progression via the activation of

PI3K-AKT

pathways. Moreover

the down-regulation of the

MAFB-NOTCH3

axis increased the sensitivity and effect of

AKT

inhibitors in osteosarcoma through significant inhibition of

AKT

phosphorylation. In conclusion

we confirmed that

MAFB

is a novel age-dependent biomarker for osteosarcoma

and targeting the

MAFB-NOTCH3

axis in combination with

AKT

inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.