北京协和医学院

Platinum drugs are used in first-line to treat ovarian cancer, but most of the patients eventually generate resistance after treatment with these drugs. Although both c-Myc and EZH2 have been implicated in regulating cisplatin resistance in ovarian cancer, the interplay between these two regulators is poorly understood. Using RNA sequence analysis (RNA-seq), for the first time we find that miR-137 level is extremely low in cisplatin resistant ovarian cancer cells, correlating with higher levels of c-Myc and EZH2 expression. Further analyses indicate that in resistant cells c-Myc enhances the expression of EZH2 by directly suppressing miR-137 that targets EZH2 mRNA, and increased expression of EZH2 activates cellular survival pathways, resulting in the resistance to cisplatin. Inhibition of c-Myc-miR-137-EZH2 pathway re-sensitizes resistant cells to cisplatin. Both in vivo and in vitro analyses indicate that cisplatin treatment activates c-Myc-miR-137-EZH2 pathway. Importantly, elevated c-Myc-miR-137-EZH2 pathway in resistant cells is sustained by dual oxidase maturation factor 1 (DUOXA1)-mediated production of reactive oxygen species (ROS). Significantly, clinical studies further confirm the activated c-Myc-miR-137-EZH2 pathway in platinum drug-resistant or recurrent ovarian cancer patients. Thus, our studies elucidate a novel role of miR-137 in regulating c-Myc-EZH2 axis that is crucial to the regulation of cisplatin resistance in ovarian cancer.

Silent mating type information regulation 1 (SIRT1), a core molecule bridging energy metabolism and ageing modulation, relies on its nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase activity and pathway crosstalk to form a key regulatory network governing ageing. This review focuses on the central regulatory role of SIRT1 in cellular senescence, integrating its multidimensional mechanisms in deoxyribonucleic acid (DNA) damage response, inflammatory microenvironment modulation, autophagic function remodeling, and maintenance of energy metabolic homeostasis. Meanwhile, we summarized the intervention strategies targeting SIRT1 (e.g., small-molecule compounds and natural extracts) and the differences in their action targets, clarifying their translational potential in the prevention and treatment of ageing-related diseases. We further highlight emerging evidence on sex-specific differences, model specificity, and evolutionary conservation that shape SIRT1’s role in ageing. This review aims to provide a systematic perspective for in-depth understanding of the SIRT1-mediated ageing regulatory network, and offer a reference for basic anti-ageing research, optimization of precise intervention strategies, and screening of therapeutic targets for related diseases.

Keloids are persistent fibroproliferative scars with an incompletely understood pathogenesis, traditionally linked to pathways such as TGF-β signaling and chronic inflammation. This review synthesizes recent literature focusing on the emerging roles of metabolic reprogramming and ferroptosis resistance in keloid fibroblasts. Recent studies highlight the convergence of these two processes as central factors sustaining the persistence and therapeutic resistance of these cells. Keloid fibroblasts exhibit cancer-like metabolic reprogramming, marked by a shift toward aerobic glycolysis, mitochondrial dysfunction, and disrupted lipid metabolism. This metabolic reorganization not only reflects the fibrotic process but also serves as a key driver of the fibroblasts' hyperproliferative, invasive, and matrix-producing characteristics. Concurrently, these fibroblasts display significant resistance to ferroptosis, an iron-dependent regulated cell death mechanism, acting as a critical survival strategy. Mechanistically, enhanced glycolysis supplies the reducing equivalents required to sustain the GPX4 antioxidant system, thereby preventing ferroptosis by neutralizing lipid peroxidation. Recognizing this integrated metabolic-ferroptotic axis shifts the therapeutic paradigm from symptomatic management to targeted, mechanism-based strategies. Interventions targeting critical nodes, such as glycolytic enzymes, or inducing ferroptosis with agents like ALA-PDT, present promising approaches to dismantle the survival advantages of keloid fibroblasts. These novel strategies offer the potential for more durable disease control, providing a foundation to overcome current translational challenges in drug delivery.

Acquired drug resistance is a major challenge for cancer therapy and is the leading cause of cancer mortality; however, the mechanisms of drug resistance are diverse and the strategy to specifically target drug-resistant cancer cells remains an unmet clinical issue. Here, we established a colorectal cancer-derived organoid biobank and induced acquired drug resistance by repeated low-level exposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysis studies revealed that chemoresistant cancer-derived organoids exhibited elevated expression of LGR4 and activation of the Wnt signaling pathway. Further, we generated a monoclonal antibody (LGR4-mAb) that potently inhibited LGR4-Wnt signaling and found that treatment with LGR4-mAb notably sensitized drug-induced ferroptosis. Mechanistically, LGR4-dependent Wnt signaling transcriptionally upregulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drug resistance. Our findings reveal that targeting of Wnt signaling by LGR4-mAb augments ferroptosis when co-administrated with chemotherapeutic agents, demonstrating a potential opportunity to fight refractory and recurrent cancers.

CD3 ligand 1 (CD3L1, ITPRIPL1), an emerging immune checkpoint, sustains immune privilege in the testis and facilitates tumor immune evasion. Targeting CD3L1 with a monoclonal antibody demonstrates potent antitumor activity in preclinical models and spontaneous tumors in companion animals. In an ongoing clinical trial, anti-CD3L1 therapy unexpectedly activated tumor-associated macrophages (TAMs) within the tumor microenvironment (TME), surpassing its anticipated role in T-cell reactivation. Mechanistic studies identified neuropilin-2 (NRP2) as the primary receptor on macrophages and uncovered the CD3L1-NRP2 axis as a critical driver of immunosuppressive M2 TAM polarization. Strikingly, in T-cell-deficient osteosarcoma models, anti-CD3L1 treatment reprogrammed TAMs toward an anti-tumor M1 phenotype, suppressing tumor progression. Clinical data corroborated these findings, revealing profound TME remodeling in advanced solid tumors. Our results elucidate a dual role for CD3L1 in immune evasion, mediated through both T-cell suppression and macrophage polarization, and highlight anti-CD3L1 as a multifaceted therapeutic strategy that enhances antigen presentation via TAM modulation.