Ting Xiao

Ferroptosis, a cell death mechanism characterized by the accumulation of lipid peroxides and subsequent membrane disruption, is emerging as a promising strategy for cancer treatment. However, many tumors, including head and neck squamous cell carcinoma (HNSCC), show resistance to ferroptosis, which reduces its therapeutic effect. Protease-activated receptors (PARs) are highly expressed in many tumors and are closely associated with tumor progression. Our study showed that the expression of protease-activated receptor 1 (PAR1) was downregulated during ferroptosis in HPV-negative HNSCC. Further studies showed that downregulation of PAR1 expression could enhance the therapeutic effect of Erastin on HPV-negative HNSCC, where PAR1 regulated the expression levels of SLC7A11, GPX4, and FTH1. In addition, we found that PAR1 activated the JAK2/STAT3 pathway in a Rac-1-dependent manner and identified STAT3 as a critical transcription factor in PAR1-mediated HPV-negative HNSCC progression and ferroptosis regulation. Inhibition of STAT3 expression attenuated the tumorigenicity of PAR1. It is worth noting that the PAR1 small molecule inhibitor Vorapaxar can further enhance the therapeutic effect of Erastin on HPV-negative HNSCC. Therefore, we propose that PAR1 participates in the progression of HPV-negative HNSCC through STAT3 and reduces the sensitivity of HPV-negative HNSCC to ferroptosis, providing a new perspective for discovering ferroptosis regulatory factors.

Context: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial disease with unknown cause and pathogenesis. Idiopathic pulmonary fibrosis patients are more likely to be concomitant with lung cancer (LC) than normal older smoking men. Currently, there is no unified expert consensus on the diagnosis and treatment of IPF combined with lung cancer (IPF-LC) patients. Evidence Acquisition: We performed a computerized search of PubMed database with keywords: idiopathic pulmonary fibrosis complicated with LC and therapy. Results: Idiopathic pulmonary fibrosis is an independent risk factor for LC, and there are similar genetic mutations, epigenetic changes, and signaling pathways between IPF and LC. acute exacerbation of IPF (AE-IPF) poses a significant challenge in the treatment of IPF-LC patients, as surgery, chemotherapy, and targeted therapy may all trigger AE-IPF leading to patient death. The clinical benefits of anti-fibrotic therapy drugs such as nintedanib or combined therapy targeting lung fibrosis and LC are expected to outweigh adverse reactions. Conclusions: Combination therapy may be an effective strategy for treating IPF-LC in the future, and there is an urgent need to develop appropriate preclinical animal models and conduct more clinical studies to find safe and effective new strategies for treating IPF-LC.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with unknown etiology, high mortality and limited treatment options. It is characterized by myofibroblast proliferation and extensive deposition of extracellular matrix (ECM), which will lead to fibrous proliferation and the destruction of lung structure. Transforming growth factor-β1 (TGF-β1) is widely recognized as a central pathway of pulmonary fibrosis, and the suppression of TGF-β1 or the TGF-β1-regulated signaling pathway may thus offer potential antifibrotic therapies. JAK-STAT is a downstream signaling pathway regulated by TGF-β1. JAK1/2 inhibitor baricitinib is a marketed drug for the treatment of rheumatoid arthritis, but its role in pulmonary fibrosis has not been reported. This study explored the potential effect and mechanism of baricitinib on pulmonary fibrosis in vivo and in vitro. The in vivo studies have shown that baricitinib can effectively attenuate bleomycin (BLM)-induced pulmonary fibrosis, and in vitro studies showed that baricitinib attenuates TGF-β1-induced fibroblast activation and epithelial cell injury by inhibiting TGF-β1/non-Smad and TGF-β1/JAK/STAT signaling pathways, respectively. In conclusion, baricitinib, a JAK1/2 inhibitor, impedes myofibroblast activation and epithelial injury via targeting the TGF-β1 signaling pathway and reduces BLM-induced pulmonary fibrosis in mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. At present, the mortality rate of the deadly disease is still very high, while the existing treatments only delay the progression of the disease and improve the quality of life of patients. Lung cancer (LC) is the most fatal disease in the world. In recent years, IPF has been considered to be an independent risk factor for the development of LC. The incidence of lung cancer is increased in the patients with IPF and the mortality is also significantly increased in the patients inflicted with the two diseases. In this study, we evaluated an animal model of pulmonary fibrosis complicated with LC by implanting LC cells orthotopically into the lungs of mice several days after bleomycin induction of the pulmonary fibrosis in the same mice. In vivo studies with the model showed that exogenous recombinant human thymosin beta 4 (exo-rhTβ4) alleviated the impairment of lung function and severity of damage of the alveolar structure by the pulmonary fibrosis and inhibited the proliferation of LC tumor growth. In addition, in vitro studies showed that exo-rhTβ4 inhibited the proliferation and migration of A549 and Mlg cells. Furthermore, our results also showed that rhTβ4 could effectively inhibit the JAK2-STAT3 signaling pathway and this might exert an anti-IPF-LC effect. The establishment of the IPF-LC animal model will be helpful for the development of drugs for the treatment of IPF-LC. Exogenous rhTβ4 can be potentially used for the treatment of IPF and LC.