Background/Aims: Lenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood. Methods: Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort. Results: Resistant HCC exhibited significant enrichment of a COLEC12high TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models. Conclusions Our work establishes the COLEC12high TAM/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.

Animals ; SARS-CoV-2 ; Antibodies, Neutralizing ; Macaca mulatta ; COVID-19/prevention & control* ; Antibodies, Viral ; Vaccines

Lumbar brucellar spondylitis is an infectious disease caused by the invasion of brucella. The incidence has been on the rise in recent years. And it threatens people's health seriously. Early and proper diagnosis and treatment is the key to cure patients with lumbar brucella spondylitis. However, in the early stage of the disease, there are only nonspecific symptoms such as back pain, fever, and sweating. If the patient has the above symptoms and epidemiological history of direct or indirect livestock contact, and inflammatory signals of the vertebrae or intervertebral space are visible on MRI, the possibility of early infection of lumbar brucella spondylitis should be considered. It is not difficult to make the diagnosis of lumbar brucella spondylitis in the middle and late stages by taking into account the epidemiology, symptoms, signs, laboratory tests, and the imaging features such as narrowing of the intervertebral space, abnormal signals of the vertebral body and disc, bone destruction and sclerosis, "lace-like" appearance, sequestrum formation and limited paraspinal abscess. Patients in these stages often present with serious manifestations such as lumbar instability due to bone destruction, and the focus is on surgical intervention. The basic principle of surgical treatment is lesion removal combined with fixation. Intraoperative reduction of damage to bone and ligamentous structures such as the posterior ligamentous complex and strong fixation will contribute to the complete cure of the disease. By referring to the literature on lumbar brucellar spondylitis, this paper focuses on the etiology, pathogenesis, clinical manifestations, imaging features, laboratory tests and conservative and surgical treatment of the disease, aiming to provide a basis for clinical diagnosis and treatment.