Background Spinal cord injury (SCI) lacks effective treatments. Ferroptosis contributes to SCI pathology. We investigated the therapeutic potential of 20-deoxyingenol (20-DOI), a natural diterpene, focusing on its role in inhibiting ferroptosis. Methods We used ventral spinal cord 4.1 motor neurons in vitro , challenged with H 2 O 2 or erastin. Assessments included cell viability, proliferation, autophagy, lysosomal function, and ferroptosis. Transcription factor EB (TFEB) knockdown validated its involvement. In vivo , a mouse SCI model assessed functional recovery (Basso mouse scale score), tissue damage, and ferroptosis markers. Results 20-DOI restored cell viability and proliferation, enhanced autophagy and lysosomal activity. It suppressed ferroptosis, reducing lipid peroxidation and reactive oxygen species, and preserving mitochondrial function. These benefits required TFEB; its knockdown abolished the protection and reduced NRF2/GPX4 levels. In mice, 20-DOI improved motor function, preserved neurons, and attenuated ferroptosis. Conclusion 20-DOI promotes recovery after SCI by activating TFEB to inhibit ferroptosis. Our work identifies TFEB as a key target and 20-DOI as a promising therapeutic agent.
Wang et al. (Wed,) studied this question.