Tissue stiffening is a predominant feature of fibrotic disorders, but the response of macrophages to changes in tissue stiffness and cellular context in fibrotic diseases remains unclear. Here, we found that the mechanosensitive ion channel Piezo1 was up-regulated in hepatic fibrosis. Macrophages lacking Piezo1 showed sustained inflammation and impaired spontaneous resolution of early liver fibrosis. Further analysis revealed an impairment of clearance of apoptotic cells by macrophages in the fibrotic liver. Macrophages showed enhanced efferocytosis when cultured on rigid substrates but not soft ones, suggesting stiffness-dependent efferocytosis of macrophages required Piezo1 activation. Besides, Piezo1 was involved in the efficient acidification of the engulfed cargo in the phagolysosomes and affected the subsequent expression of anti-inflammation genes after efferocytosis. Pharmacological activation of Piezo1 increased the efferocytosis capacity of macrophages and accelerated the resolution of inflammation and fibrosis. Our study supports the antifibrotic role of Piezo1-mediated mechanical sensation in liver fibrosis, suggesting that targeting PIEZO1 to enhance macrophage efferocytosis could induce fibrosis regression.

Inflammasome, a multiprotein complex that regulates interleukin (IL)‑1β secretion and pyroptosis, participates in numerous inflammatory diseases, including sepsis, atherosclerosis and type‑2 diabetes. Investigating the inflammasome regulation is therefore crucial to understand the inflammasome activation and develop treatment for the related diseases. In addition, it remains unknown how the inflammasome is naturally suppressed during the inflammatory process. The present study aimed to investigate the role of resolvin D2 (RvD2), an innate suppressor of inflammation produced from essential ω3‑polyunsaturated fatty acids, in the activation of the inflammasome via in vitro and in vivo experiments. The effects of RvD2 on the cytokine production of inflammasome‑related peritonitis were determined, and the NLRP3 inflammasome activation was investigated in the presence of RvD2. Moreover, the potential mechanisms underlying RvD2 in NLRP3 inflammasome regulation through autophagy and proteasome were investigated. The results of the present study demonstrated that RvD2 suppressed inflammasome‑mediated peritonitis in vivo and regulated the NLR family pyrin domain containing 3 (NLRP3) inflammasome, but not in absent in melanoma 2 (AIM2), NLR family CARD domain containing 4 (NLRC4) inflammasomes. Mechanistically, RvD2 was found to promote the degradation of NLRP3 through autophagy, and the inhibition of autophagy could reverse the RvD2‑mediated suppression of NLRP3 inflammasome in vitro and partially reverse the inflammasome‑mediated peritonitis in vivo. In summary, the present study reported the negative regulation of NLRP3 inflammasome activation by RvD2. The findings from this study may extend the knowledge of the innate regulation of inflammasome and highlight a possible target for inflammasome‑related diseases.

Introduction: Small cell lung cancer (SCLC) transformation serves as a significant mechanism of resistance to tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. To address this clinical challenge, we conducted a retrospective analysis at Zhejiang University School of Medicine, the First Affiliated Hospital, focusing on patients with EGFR sensitizing mutations.Methods: A total of 1012 cases were included in this retrospective analysis. The cohort primarily consisted of patients with EGFR sensitizing mutations. Biopsy-confirmed small cell transformation was observed in seven patients, accounting for 0.7% of the cases. All patients in this subset were initially diagnosed with stage IV adenocarcinoma (ADC), with four cases classified as poorly differentiated and three as moderately to poorly differentiated ADC. EGFR exon 19 deletions were identified in five of these cases. Next-generation sequencing (NGS) was performed on seven cases, revealing mutations in the tumor protein p53 (TP53) gene in four cases and loss of the retinoblastoma1 (RB1) gene in three cases.Results: The median duration from the initial diagnosis to small cell transformation was 35.9 months (interquartile range: 12.1–84 months). Following small cell transformation during EGFR inhibition, all patients received etoposide/platinum-based treatment, leading to a median progression-free survival (PFS) of 4.7 months (interquartile range: 2.7–10.1 months). Notably, most patients in this series had poorly differentiated adenocarcinomas at the outset. TP53 mutations and RB1 loss were common genetic alterations observed in patients with small cell transformation in this cohort.Discussion: The findings underscore the clinical significance of SCLC transformation as a resistance mechanism to EGFR TKIs in NSCLC with EGFR mutations. The observed genetic alterations, including TP53 mutations and RB1 loss, suggest potential associations with the transformation process and warrant further investigation. Understanding the genetic landscape and clinical outcomes in patients experiencing small cell transformation can contribute to improved strategies for managing resistance in EGFR-mutant NSCLC.

Synchronous multiple primary malignant tumors (MPMTs) are rare in young adults. Genomic profiling of synchronous MPMTs has not been systematically investigated to elucidate their genetic associations, but may be important to assist diagnosis and guide appropriate treatment strategy. In the present study, mutation profiling was performed using targeted next generation sequencing (NGS) on 416 cancer‑related genes in synchronous triple primary tumors of the lung, kidney and thyroid in a 32‑year‑old female patient. The patient was diagnosed with moderately differentiated lung adenocarcinoma (T2aN0M0; stage IB), renal clear cell carcinoma (T1aN0M0; stage I), and thyroid papillary carcinoma (T1N1aM0, stage III) by pathological assessments. Clinically actionable mutations in EGFR and BRAF genes were identified in the lung and the thyroid lesions, respectively. Three tumors demonstrated distinct genomic profiles, suggesting that all tumors were independent primary tumors, which was consistent with histopathological assessment. Three potential germline cancer susceptibility mutations were shared between this patient and her father who was diagnosed with lung cancer. The present results demonstrated that, in the context of identical germline background and environmental exposure, multiple synchronous tumors in the same patient may have distinct mutation profiles and can be driven by distinct molecular events. Combination therapies may need to be considered during treatment decision‑making.

NF-κB-inducing kinase (NIK) is primarily recognized for its role as the apical kinase that activates non-canonical NF-κB signaling and its involvement in immune system regulation. NIK is crucial for maintaining cellular health by regulating fundamental processes such as differentiation, growth, and survival. Emerging evidence suggests that dysregulated expression or function of NIK in non-lymphoid cells is a key factor in cancer progression. While NIK deficiency causes severe immune dysfunction, its overexpression or excessive activation is linked to inflammatory diseases, metabolic disorders, and cancer development. The development of small molecule inhibitors targeting NIK has sparked optimism for clinical intervention, positioning NIK as a promising druggable mediator for cancer. The ongoing progress in creating novel small molecule NIK inhibitors offers new opportunities for testing NIK-targeted cancer therapies, potentially advancing the clinical application of NIK-based cancer treatments.