The circ_0074371/miR-4738-3p/AMPK Signaling Axis Induces M1 Macrophage Polarization and Restricts Intracellular Survival of Mycobacterium tuberculosis

Zhang, J.-a.; Lian, C.-Y.; Lu, Y.-B.; Yao, S.-Y.; Xu, H.; Xu, Y.; Liu, G.-B.; Chen, G.-S.; Cen, Y.-F.; Li, Y.-T.; Xu, Z.-L.; Huang, Y.-D.; Chen, G.-Y.; Wang, J.-J.; Shi, J.-H.; Gao, Y.-C.; Cai, X.-Z.; Liang, J.; Huang, W.-C.; Zhang, Z.-P.; Pi, J.; Xu, J.-F.

doi:10.64898/2026.10.20.760595

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bioRxiv · 10.64898/2026.10.20.760595

The circ_0074371/miR-4738-3p/AMPK Signaling Axis Induces M1 Macrophage Polarization and Restricts Intracellular Survival of Mycobacterium tuberculosis

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Abstract

Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis, remains endemic in regions where it is prevalent. Mycobacterium tuberculosis is an intracellular pathogen that can survive within host macrophages; however, the mechanisms governing its long-term persistence and the progression to active pulmonary tuberculosis remain poorly understood. Circular RNAs (circRNAs) have been implicated in the initiation and progression of numerous diseases. In our previous study, circRNA sequencing identified several circRNAs associated with tuberculosis progression. In the present study, sequencing and reverse transcription-polymerase chain reaction (RT-PCR) analyses revealed that Circ_0074371 was significantly downregulated in monocytes from patients with active pulmonary tuberculosis (ATB) and was closely associated with disease onset and progression, exhibiting considerable diagnostic value for ATB. Functional experiments further showed that Circ_0074371 significantly impaired the intracellular survival of Mtb and promoted M1 macrophage polarization. Mechanistically, Circ_0074371 acted as a competing endogenous RNA by sequestering miR-4738-3p, a potent negative regulator of AMP-activated protein kinase (AMPK) activation. Collectively, these findings identify Circ_0074371 as a tuberculosis-associated circRNA that regulates AMPK activity and reveal a novel mechanism through which Circ_0074371 influences macrophage polarization via the AMPK pathway, providing new insights into potential therapeutic targets for ATB.

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Zhang, J.-a., Lian, C.-Y., Lu, Y.-B., Yao, S.-Y., Xu, H., Xu, Y., Liu, G.-B., Chen, G.-S., Cen, Y.-F., Li, Y.-T., Xu, Z.-L., Huang, Y.-D., Chen, G.-Y., Wang, J.-J., Shi, J.-H., Gao, Y.-C., Cai, X.-Z., Liang, J., Huang, W.-C., Zhang, Z.-P., Pi, J., Xu, J.-F.. 2026-10-26. The circ_0074371/miR-4738-3p/AMPK Signaling Axis Induces M1 Macrophage Polarization and Restricts Intracellular Survival of Mycobacterium tuberculosis. https://doi.org/10.64898/2026.10.20.760595

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