Cardiac hypertrophy is a precursor to heart failure and represents a significant global cause of mortality, thereby necessitating timely and effective therapeutic interventions. Zinc finger protein 36 (Zfp36) is recognised as a critical regulator of ferroptosis; however, its role and underlying mechanisms in cardiac hypertrophy remain largely unexplored. This study aims to investigate the regulatory function of Zfp36 in ferroptosis within the context of cardiac hypertrophy.
Single-cell sequencing analysis demonstrated a reduction in Zfp36 expression associated with cardiac hypertrophy. Zfp36 was observed to mitigate ferroptosis and reduce hypertrophic phenotypes in cardiomyocytes subjected to Angiotensin II (Ang II) and in myocardial tissues induced by transverse aortic constriction. The ferroptosis inhibitor Ferrostatin-1 was shown to alleviate hypertrophy when co-incubated with si-Zfp36 and Ang II. Mechanistically, Zfp36 binds to the 3′ untranslated region (3′UTR) of Ythdc2 mRNA, facilitating its degradation. Ythdc2 subsequently binds to SLC7A11 mRNA, enhancing its decay, which leads to a reduction in glutathione (GSH) levels, thereby exacerbating ferroptosis and cardiac hypertrophy. Furthermore, overexpression of Ythdc2 reversed the protective effects conferred by Zfp36, while silencing of Ythdc2 counteracted the effects of Zfp36 knockdown.
This study elucidates the role of Zfp36 in cardiac hypertrophy, specifically detailing its modulatory mechanism via the Ythdc2/SLC7A11/GSH ferroptosis pathway. These insights lay the groundwork for innovative approaches to understanding the pathological mechanisms underlying cardiac hypertrophy and enhancing clinical interventions.
Basic research identified oncogenic driver mutations in lung cancer (LC). However, <10% of patients carry driver mutations. Thus, most patients are not recommended for first-line kinase inhibitor (KI)–based therapies. Through enabling technologies and bioinformatics, we gained deep insight into patient-specific signalling networks which permitted novel KI-based treatment options in LC.
We performed molecular pathology, transcriptomics and miRNA profiling across 95 well-characterized LC patients. We confirmed results based on cross-linked immunoprecipitation-sequencing data, and used N = 524 adeno- and 497 squamous cell carcinomas as validation sets. We employed the PamGene platform to identify aberrant kinases, validated the results by evaluating independent siRNA and CRISPR-mediated mRNA knockdown studies in human LC cell lines.
Transcriptomics revealed 439, 1240, 383 and 320 significantly upregulated genes, respectively, for adeno-, squamous, neuroendocrine and metastatic cases, and there are 1092, 1477, 609 and 1267 downregulated DEGs. Based on gene enrichment analysis and experimentally validated miRNA–gene interactions, we constructed regulatory networks specific for adeno-, squamous, neuroendocrine and metastatic LC. Molecular profiling discovered 137 significantly upregulated kinases (range 2–26-fold) of which 65 and 72, respectively, are tyrosine and serine-threonine kinases while 6 kinases carry driver mutations. Meanwhile, there are 21 kinases commonly upregulated irrespective of the histological type of LC. Bioinformatics decoded networks in which kinases function as master regulators. Typically, the networks consisted of 14, 9, 16 and 19 highly regulated kinases in adeno-, squamous, neuroendocrine and metastatic LC. Inhibition of kinases which function as master regulators disrupted the signalling networks, and their gene knock-down studies confirmed inhibition of cell proliferation in a panel of human LC cell lines. Additionally, the proposed molecular profiling enables KI-based therapies in patients with acquired drug resistance.
Our study broadens the perspective of KI-based therapies in LC, and we propose a framework to overcome acquired drug resistance.
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