Patients with densely innervated tumors suffer with poor outcomes, thus identifying them could define a cohort that could benefit from aggressive treatments. Most cases and deaths from ovarian cancer are associated with high-grade serous ovarian carcinoma (HGSOC). We immunohistochemically analyzed the histological subtypes of ovarian cancer (high-grade serous, low-grade serous, clear cell, mucinous, and endometrioid) for nerves; only HGSOCs were densely innervated. We previously defined that tumor-released small extracellular vesicles (sEVs) recruit nerves to the tumor bed and thus tested whether the difference in nerve infiltration amongst ovarian cancers was associated with sEVs. Using an in vitro neurite outgrowth assay, we found that HGSOC sEVs harbored robust neurite outgrowth activity. Importantly, sEVs from fallopian tube cell lines (the primary cell of origin of HGSOC) predominantly lacked this activity. Implantation of a syngeneic mouse model of HGSOC into transgenic mice lacking tumor-infiltrating nerves slowed tumor growth, sensitized disease to carboplatin, and improved survival. Consistent with this, we show that recurrent, treatment-resistant disease in patients is significantly more innervated than its matched naïve (untreated) malignancy. Taken together, these data identify dense nerve infiltration of HGSOCs and show that innervation contributes to treatment resistance.

Amyloid-β (Aβ) aggregation is targeted with small molecules as a pathway toward developing potential Alzheimer's disease (AD) therapies. Resveratrol, a natural polyphenol, has been proposed as an inhibitor of Aβ aggregation, but its mechanistic effects across distinct Aβ42 aggregates remain unresolved. To better evaluate resveratrol's potential to treat AD, here we focus on molecular-level insights into the mechanisms that underlie its interaction with several distinct classes of Aβ42 aggregates. In contrast to published approaches that are based on monitoring the evolution of the total fibrillar mass, we employ time-resolved in situ atomic force microscopy to explore the effects of resveratrol on Aβ42 amyloid and non-amyloid assemblies. While data suggest a weak interaction between resveratrol and low-molecular-weight Aβ42 species, we also observe a concentration-dependent reduction in fibrillization. In the presence of resveratrol, we observe a decrease in fibril thickness and end-dependent slowing of elongation; furthermore, the fibrils exhibit reduced mechanical integrity and fragment under minimal scanning stress. Importantly, resveratrol does not affect the formation or morphology of oligomers and amorphous aggregates. These findings suggest that resveratrol selectively targets the fibril pathway while leaving oligomeric assemblies unaltered. The results provide mechanistic insights into the differential effects of small molecules on Aβ42 assemblies and establish a framework for evaluating inhibitors of aggregation with single-aggregate resolution.

Viral myocarditis (VMC) is a myocardial injury syndrome caused by enterovirus infections, including Coxsackievirus B5 (CVB5) and Echovirus 6 (ECHO6). However, the exact pathogenesis of VMC by enteroviruses remains unclear. Here, the host immune response differences in transcriptomics in human cardiomyocyte AC16 cells upon CVB5 and ECHO6 infections were explored. CVB5 and ECHO6 effectively infected AC16 cells, showing significant viral replication and cytopathic effects at 48 h post-infection. Transcriptomic analysis indicated that both CVB5 and ECHO6 infection induced a series of immune- and inflammation- related genes, including IL6, CCL3, and IFNL1, which were validated by qPCR. Additionally, Ribavirin demonstrated a certain inhibitory effect on the viral replication of both CVB5 and ECHO6 at a concentration of 50 µm. This study established a systematic comparison of the common transcriptomic differences and immune response characteristics of both CVB5 and ECHO6 infection in human cardiomyocytes. The marked upregulation of immune-related genes suggests that innate immunity and the inflammatory response play critical roles in cardiomyocytes defense against enterovirus infection. Ribavirin showed notable inhibitory activity against both CVB5 and ECHO6. The study sheds light on new insights into the foundations for the pathogenesis of enterovirus-associated VMC and the development of promising therapeutic approaches against VMC.

Short hairpin RNA of lncDlx6-os1 (sh-lncDlx6os1) and small interfering RNA of Parkin (si-Parkin) were used to inhibit the expression of lncDlx6-os1 and Parkin in cardiomyocytes, respectively. qRT-PCR, western blotting, and flow cytometry were performed to investigate the underlying mechanism. sh-lncDlx6os1 inhibited HG-induced reactive oxygen species (ROS) generation and increased the expression of HO-1 and NRF2 in HG-treated cardiomyocytes. sh-lncDlx6os1 significantly suppressed the expression of the apoptotic molecule caspase3, and increased the expression of the anti-apoptotic molecule Bcl-2, thereby inhibiting HG-induced apoptosis. Meanwhile, sh-lncDlx6os1 increased the expression of Sirt1, PINK1, Parkin, and LC3II/LC3I in HG-treated cardiomyocytes. Suppression of Parkin by si-Parkin weakened the regulatory effect of sh-lncDlx6os1 on apoptosis and caspase3 and Bcl-2 expression. si-Parkin also attenuated the inhibitory effect of sh-lncDlx6os1 on ROS generation and increased HO-1 and NRF2 expressions in HG-treated cardiomyocytes. Our study revealed that the suppression of lncDlx6os1 significantly alleviated HG-induced oxidative stress, which was partially mediated by parkin in cardiomyocytes.

Feiwei Mixture (FWHJ), a hospital preparation for lung cancer, lacks a defined mechanism of action. Using Lewis lung carcinoma (LLC) tumor-bearing mice and an LLC-CD8+ T cell co-culture model, we evaluated the effects of FWHJ on tumor growth, T cell infiltration, and apoptosis. Key signaling molecules (NR1D1, cGAS-STING, SOCS3-JAK-STAT3) and chemokines were analyzed using Western blot, flow cytometry, and immunoassays. Further knockout of NR1D1 confirmed its critical role in mediating the anti-tumor effects of FWHJ. FWHJ dose-dependently inhibited tumor growth in mice and enhanced CD4+/CD8+ T cell infiltration. It upregulated NR1D1, SOCS3, and the cGAS-STING pathway, while suppressing JAK-STAT3 signaling, leading to increased CCL5, CXCL10, and IFN-α. In co-culture model, FWHJ-containing serum promoted LLC cell apoptosis and suppressed malignant progression, recapitulating the signaling alterations observed in vivo. Crucially, NR1D1 knockout abolished the therapeutic effects of FWHJ. FWHJ inhibits non-small cell lung cancer (NSCLC) by activating NR1D1 to stimulate the cGAS-STING pathway and suppress the JAK-STAT3 signaling axis, thereby enhancing anti-tumor immunity. This study provides a foundation for further investigation into the anti-tumor mechanisms of FWHJ and establishes a scientific basis for its potential application in lung cancer therapy.

Ischemia-reperfusion injury remains a major challenge in modern regenerative medicine due to its complex mechanisms, lack of effective therapies, and persistent constrains to translating new interventions from bench to bedside. Currently, there are no FDA-approved drugs that directly target ischemia-reperfusion injury, highlighting a substantial therapeutic gap. While restoring blood flow is vital for salvaging ischemic tissue, the reperfusion process paradoxically triggers additional cellular damage. The clinical significance and complexity of ischemia-reperfusion injury underscore an urgent need for mechanistically targeted therapeutic approaches. Recent research has identified pivotal molecular targets-PHLDA1, SIRT6, PKM2, and ubiquitin-specific proteases (USPs)-that play key roles in modulating cellular responses such as oxidative stress, inflammation, metabolism, apoptosis, autophagy, ferroptosis, and blood-brain barrier dysfunction during ischemia reperfusion injury. Advances in understanding these mechanisms offer promising strategies for developing novel interventions to mitigate tissue damage and improve patient outcomes. This review critically examines these molecular targets, detailing recent advances and outlining future directions in ischemia reperfusion injury research.

The next-generation anti-cancer therapeutics must disrupt intracellular mechanics, efficiently eradicating cancer cells, rather than simply intoxicating them. We evaluate the mechanism of action of PCMS, a PAMAM-based supramolecule that eradicates cancer cells by reorganizing their internal mechanics rather than their genes. Once internalized, PCMS self-assembles into a perinuclear ring that severs nucleus-cytoskeleton communication. We observed PCMS's dual-intelligent mechanisms of action: Cytoskeletal rescue, where actin-microtubule filaments move towards the PCMS ring, treating it as a surrogate plasma membrane, attempting to restore vesicular trafficking; Nuclear counter-expansion, where chromatin-lamina condensates undergo stepwise viscoelastic transitions that push the nuclear envelope outward to reestablish membrane contact. These contradictory forces amplify mechanical stress, driving super-critical strain and nuclear lysis without broad transcriptional modulations. By geometry alone, PCMS collapses the actin-microtubule-nucleus continuum and turns the cell's adaptive machinery into its own executioner. The discovery that life and death decisions can be reprogrammed through spatial conflict establishes a paradigm of mechanical deception, inaugurating a new class of cellular adaptive feedback-targeted mechanotherapeutics that overcome resistance by exploiting the cell's own morphogenetic logic.

Breast cancer bone metastasis often involves a prolonged dormancy phase, during which disseminated tumor cells (DTCs) remain undetectable and resistant to conventional therapies, posing a significant risk for late recurrence. Understanding the underlying mechanisms of tumor dormancy and reactivation is crucial for developing effective clinical interventions. However, current clinical translation faces multiple challenges, including limitations in detecting dormant tumor cells, insufficient biomarkers for dormancy, and difficulties in targeted drug delivery. Recent advances in elucidating the mechanisms of dormancy-such as the establishment of the pre-metastatic niche, intercellular communication in the bone marrow microenvironment, and signaling pathways regulating dormancy and reactivation-have provided novel therapeutic targets. Based on these mechanistic insights, nanotechnology-based drug delivery systems have emerged as promising strategies to precisely target dormant breast cancer cells in bone marrow niches. In this review, we summarize the current understanding of dormancy mechanisms in breast cancer bone metastasis, discuss the barriers hindering clinical translation, and highlight how mechanism-driven nanotherapeutic strategies may offer new opportunities to prevent recurrence by targeting dormant tumor cells.

CDCA3 and TWIST1 are implicated in cell-cycle control and transcriptional regulation, yet their combined role in lung adenocarcinoma (LUAD) remains unclear. Here, we investigated the impact of the TWIST1/CDCA3 axis on LUAD cell behavior. Leveraging TCGA and KnockTF v2.0, we pinpointed TWIST1 as an upstream driver of CDCA3 in LUAD and delineated associated survival outcomes. ChIP and dual-luciferase assays verified the interaction between CDCA3 and TWIST1. We also quantified CDCA3 and TWIST1 mRNA by qRT-PCR and determined CDCA3, the immune-therapy biomarker PD-L1, and EMT-related protein levels by Western blot. Furthermore, CCK-8, colony formation assays, wound healing, and Transwell assays were conducted to evaluate the malignant behaviors of cells. Bioinformatic and functional analyses revealed that both CDCA3 and TWIST1 were highly expressed in LUAD, and their elevated levels predicted poor prognosis. Further investigation identified TWIST1 as an upstream activator of CDCA3. Knockdown of TWIST1 attenuated the malignant phenotype and reduced PD-L1 expression in LUAD cells, whereas subsequent overexpression of CDCA3 fully reversed these suppressive effects. This study aims to validate that the TWIST1/CDCA3 axis promotes invasion, migration, proliferation, and PD-L1 expression of LUAD cells.