Targeting NSCLC drug resistance: Systems biology insights into the MALAT1/miR-145-5p axis and Wip1 in regulating ferroptosis and apoptosis

The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) and microRNA-145-5p (miR-145) axis play a pivotal role in regulating drug resistance, apoptosis and senescence in non-small cell lung cancer (NSCLC). MALAT1 drives drug resistance by suppressing miR-145 and activating MUC1, thereby inhibiting ferroptosis; however, its precise role in regulating ferroptosis in NSCLC remains unclear. Therefore, we propose a computational modelling approach to unravel the impact of the MALAT1/miR-145 axis on ferroptosis and drug resistance, to identify potential therapeutic strategies that promote ferroptosis. Using Boolean logic and a stochastic updating scheme, we developed and validated a robust regulatory model that encompasses ferroptosis, apoptosis, senescence and drug resistance pathways. The model, based on extensive literature and validated through gain- and loss-of-function perturbations, demonstrated strong alignment with observed clinical data that were not included in its construction. Our analysis identified three previously unreported feedback loops, miR-145/Wip1/p53, miR-145/Myc/MALAT1 and miR-145/MUC1/BMI1, establishing miR-145 as a central regulator in NSCLC. Perturbations targeting MALAT1 and wild-type p53-induced phosphatase 1 (Wip1) revealed potential therapeutic opportunities, with miR-145 activation emerging as a promising strategy to induce ferroptosis and overcome drug resistance. These findings highlight the MALAT1/miR-145 axis as a transformative therapeutic target, presenting a computational foundation to advance NSCLC treatment strategies.