Gupta Shantanu, Silveira Daner Acunha, Mombach José Carlos, Hashimoto Ronaldo F
Department of Computer Science, University of Sao Paulo, Sao Paulo, Brazil.
Children's Cancer Institute, Porto Alegre, Rio Grande do Sul, Brazil.
J R Soc Interface. 2025 May;22(226):20240852. doi: 10.1098/rsif.2024.0852. Epub 2025 May 28.
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.
长链非编码RNA转移相关肺腺癌转录本1（lncRNA MALAT1）与微小RNA-145-5p（miR-145）轴在调节非小细胞肺癌（NSCLC）的耐药性、细胞凋亡和衰老过程中发挥着关键作用。MALAT1通过抑制miR-145并激活MUC1来驱动耐药性，从而抑制铁死亡；然而，其在NSCLC中调节铁死亡的确切作用仍不清楚。因此，我们提出一种计算建模方法，以阐明MALAT1/miR-145轴对铁死亡和耐药性的影响，从而确定促进铁死亡的潜在治疗策略。利用布尔逻辑和随机更新方案，我们开发并验证了一个强大的调控模型，该模型涵盖了铁死亡、细胞凋亡、衰老和耐药性途径。该模型基于大量文献，并通过功能获得和功能缺失扰动进行了验证，与构建模型时未纳入的观察到的临床数据显示出高度一致性。我们的分析确定了三个以前未报道的反馈回路，即miR-145/Wip1/p53、miR-145/Myc/MALAT1和miR-145/MUC1/BMI1，确立了miR-145作为NSCLC中的核心调节因子。针对MALAT1和野生型p53诱导的磷酸酶1（Wip1）的扰动揭示了潜在的治疗机会，激活miR-145成为诱导铁死亡和克服耐药性的有前景的策略。这些发现突出了MALAT1/miR-145轴作为一个变革性的治疗靶点，为推进NSCLC治疗策略提供了一个计算基础。
