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With a complex and often misunderstood etiology, acute Charcot neuroarthropathy (ACN) is a devastating complication of peripheral neuropathy. In patients with diabetes, timely diagnosis of ACN in the foot and ankle is essential to prevent loss of both limb and life. Herein, the authors evaluate the growing body of evidence in identifying targeted pathways for future therapeutic interventions. A literature search was conducted through the PubMed research database. Searched terms included 'Charcot,' 'foot and ankle,' 'neuroarthropathy,' 'p