Naotaifang Formula Suppresses Ferroptosis by Ameliorating Mitochondrial Biogenesis Through the Nrf2/TFAM Pathway in...

This study aimed to investigate whether activating the Nrf2/TFAM pathway boosts mitochondrial biogenesis, reduces ferroptosis in ischemic stroke (IS), and evaluates Naotaifang (NTF) formula's therapeutic potential.

Ferroptosis and mitochondrial biogenesis indicators were measured at various time points following MCAO. Various methods, including transmission electron microscopy, immunofluorescence assay, enzyme-linked immunosorbent assay, Western blotting assays, and real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR), were employed to evaluate the impact of NTF on mitochondrial biogenesis and ferroptosis in vivo and in vitro.

IS significantly inhibits mitochondrial biogenesis and increases neuronal ferroptosis, with brain damage worsening over time. MCAO groups showed reduced expression of Nrf2, TFAM, ATP, CISD2, FPN, GPX4, SOD, and HO-1, alongside elevated Fe²⁺, ROS, and LPO (P < 0.05) compared to the control group. Both sulforaphane and NTF treatment reversed these effects; NTF treatment effectively increased the expression of Nrf2, TFAM, FtMt, CISD1, CISD2, FPN, and GPX4 while inhibiting the levels of Fe²⁺, ROS, and LPO. (P < 0.05).

This finding clarifies mitochondrial biogenesis's crucial role, proposes a new "pathway + molecule" strategy for IS treatment, and supports NTF's clinical potential, though larger animal models and long-term safety studies are needed.

In the context of IS, reduced mitochondrial biogenesis plays an important role in ferroptosis. Targeting the Nrf2/TFAM signaling pathway may improve mitochondrial biogenesis in IS. Furthermore, NTF can mitigate ferroptosis by promoting mitochondrial biogenesis through the Nrf2/TFAM signaling pathway.