Ferritin, a key regulator of iron homeostasis in macrophages, has been reported to confer host defenses against Mycobacterium tuberculosis (Mtb) infection. Nuclear receptor coactivator 4 (NCOA4) was recently identified as a cargo receptor in ferritin degradation. Here, we show that Mtb infection enhanced NCOA4-mediated ferritin degradation in macrophages, which in turn increased the bioavailability of iron to intracellular Mtb and therefore promoted bacterial growth. Of clinical relevance, the upregulation of FTH1 in macrophages was associated with tuberculosis (TB) disease progression in humans. Mechanistically, Mtb infection enhanced NCOA4-mediated ferritin degradation through p38/AKT1- and TRIM21-mediated proteasomal degradation of HERC2, an E3 ligase of NCOA4. Finally, we confirmed that NCOA4 deficiency in myeloid cells expedites the clearance of Mtb infection in a murine model. Together, our findings revealed a strategy by which Mtb hijacks host ferritin metabolism for its own intracellular survival. Therefore, this represents a potential target for host-directed therapy against tuberculosis.

Four new compounds including two new sesquiterpenoid dimers, commiphoroids E (1) and F (2), a new triterpenoid (3), and a new sesquiterpenoid (4), along with three known terpenoids (5−7) were isolated from Resina Commiphora, whose structures were identified by NMR spectra, HRESIMS, and X-ray diffraction analysis. Compounds 1 and 2 both bear an O-bridge ring and feature a plausible [4 + 2] Diels–Alder cycloaddition reaction. Antimycobacterial activities show that all the tested compounds (200 μM) could inhibit the growth of both sensitive and clinically multi-drug resistant (MDR) isolated strains. In addition, cellular toxicity of the isolates against human cancer cells and THP-1 monocyte cells was examined.