Targeting the hsa-miR-155-5p–BACH1–MMP-9 Signaling Hub in Lung Cancer: A Novel Anticancer Mechanism of Thymoquinone

Khan, Yusuf Saleem; Farhana, Aisha; Alnajib, Alfatih Mohamed Ahmed; Khaja, Azharuddin Sajid Syed; Nagi, Hatim Adam; Ginawi, Tarig; Osman, Abuzar Abdulwahab; Alameen, Ayman Ali Mohammed; Manni, Emad; Rasheed, Zafar

doi:10.3390/biom16070955

Open AccessArticle

Targeting the hsa-miR-155-5p–BACH1–MMP-9 Signaling Hub in Lung Cancer: A Novel Anticancer Mechanism of Thymoquinone

by

Yusuf Saleem Khan

^1,*

,

Aisha Farhana

^2,*

,

Alfatih Mohamed Ahmed Alnajib

³,

Azharuddin Sajid Syed Khaja

⁴

,

Hatim Adam Nagi

⁵,

Tarig Ginawi

⁶,

Abuzar Abdulwahab Osman

⁷,

Ayman Ali Mohammed Alameen

²

,

Emad Manni

² and

Zafar Rasheed

⁸

¹

Department of Anatomy, College of Medicine, University of Ha’il, Ha’il 55476, Saudi Arabia

²

Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia

³

Department of Surgery, College of Medicine, University of Ha’il, Ha’il 55476, Saudi Arabia

⁴

Department of Pathology, College of Medicine, University of Ha’il, Ha’il 55476, Saudi Arabia

⁵

Department of Family and Community Medicine, College of Medicine, University of Ha’il, Ha’il 55476, Saudi Arabia

⁶

Department of Biochemistry, College of Medicine, University of Ha’il, Ha’il 55476, Saudi Arabia

⁷

Department of Pharmacology, College of Medicine, University of Ha’il, Ha’il 55476, Saudi Arabia

⁸

LTT-LabTech Training Centre, 28 Russell St, South Brisbane, QLD 4101, Australia

^*

Authors to whom correspondence should be addressed.

Biomolecules 2026, 16(7), 955; https://doi.org/10.3390/biom16070955

Submission received: 12 May 2026 / Revised: 18 June 2026 / Accepted: 24 June 2026 / Published: 27 June 2026

(This article belongs to the Special Issue Signal Transduction and Pathway Regulation in Cancer)

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Abstract

Objective: Lung cancer (LC) remains a leading cause of cancer mortality worldwide. Thymoquinone (TQ), a bioactive compound derived from Nigella sativa, possesses anti-inflammatory and antioxidant properties, but its precise mechanisms concerning miRNA regulation in LC are poorly defined. This study investigates the anti-cancer potential of TQ through modulation of microRNA signaling in LC. Methods: We employed an integrated approach combining bioinformatic predictions with rigorous experimental validation in A549 lung adenocarcinoma cells and SHP-77 human small-cell lung carcinoma (SCLC) cells. Bioinformatic analyses predicted miRNA targets, and experimental techniques included dual-luciferase reporter assays, miRNA inhibition, TaqMan RT-qPCR, cell-based ELISA, and Western blotting to dissect the molecular pathway. Results: We identified the transcription factor BACH1 as a direct and novel target of hsa-miR-155-5p. TQ potently suppressed interferon-γ-induced expression of both hsa-miR-155-5p and its target, BACH1. This TQ-mediated suppression led to subsequent downregulation of the key metastasis-promoter Matrix Metalloproteinase-9 (MMP-9). Genetic inhibition of miR-155-5p or direct BACH1 inhibition phenocopied the effects of TQ, confirming the functional significance of this axis. Thus, we define a novel oncogenic signaling cascade—the hsa-miR-155-5p/BACH1/MMP-9 axis that is effectively disrupted by TQ. Conclusions: This represents the first evidence that TQ exerts its anti-cancer effects in LC through the modulation of the critical signaling cascade (hsa-miR-155-5p → BACH1 → MMP-9). Our findings establish TQ as a multi-targeted agent capable of simultaneously inhibiting miRNA-mediated oncogenic signaling and protein-level effectors. The dual therapeutic action of TQ represents a novel therapeutic strategy and underscores its potential for synergistic combination therapies.

Keywords: lung neoplasm; microRNA-155; thymoquinone; BACH1; MMP-9; neoplasm metastasis; inflammation mediators; natural compounds in cancer therapy

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MDPI and ACS Style

Khan, Y.S.; Farhana, A.; Alnajib, A.M.A.; Khaja, A.S.S.; Nagi, H.A.; Ginawi, T.; Osman, A.A.; Alameen, A.A.M.; Manni, E.; Rasheed, Z. Targeting the hsa-miR-155-5p–BACH1–MMP-9 Signaling Hub in Lung Cancer: A Novel Anticancer Mechanism of Thymoquinone. Biomolecules 2026, 16, 955. https://doi.org/10.3390/biom16070955

AMA Style

Khan YS, Farhana A, Alnajib AMA, Khaja ASS, Nagi HA, Ginawi T, Osman AA, Alameen AAM, Manni E, Rasheed Z. Targeting the hsa-miR-155-5p–BACH1–MMP-9 Signaling Hub in Lung Cancer: A Novel Anticancer Mechanism of Thymoquinone. Biomolecules. 2026; 16(7):955. https://doi.org/10.3390/biom16070955

Chicago/Turabian Style

Khan, Yusuf Saleem, Aisha Farhana, Alfatih Mohamed Ahmed Alnajib, Azharuddin Sajid Syed Khaja, Hatim Adam Nagi, Tarig Ginawi, Abuzar Abdulwahab Osman, Ayman Ali Mohammed Alameen, Emad Manni, and Zafar Rasheed. 2026. "Targeting the hsa-miR-155-5p–BACH1–MMP-9 Signaling Hub in Lung Cancer: A Novel Anticancer Mechanism of Thymoquinone" Biomolecules 16, no. 7: 955. https://doi.org/10.3390/biom16070955

APA Style

Khan, Y. S., Farhana, A., Alnajib, A. M. A., Khaja, A. S. S., Nagi, H. A., Ginawi, T., Osman, A. A., Alameen, A. A. M., Manni, E., & Rasheed, Z. (2026). Targeting the hsa-miR-155-5p–BACH1–MMP-9 Signaling Hub in Lung Cancer: A Novel Anticancer Mechanism of Thymoquinone. Biomolecules, 16(7), 955. https://doi.org/10.3390/biom16070955

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Targeting the hsa-miR-155-5p–BACH1–MMP-9 Signaling Hub in Lung Cancer: A Novel Anticancer Mechanism of Thymoquinone

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