The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models. These glucocorticoid-response elements are primed by the pioneer transcription factor PU.1, which interacts with the glucocorticoid receptor. Eviction of PU.1 promotes receptor binding, increasing the expression of genes involved in apoptosis and facilitating a stronger therapeutic response. Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.

As a member of the melanocortin receptor family, melanocortin 4 receptor (MC4R) plays a critical role in regulating energy homeostasis and feeding behavior, and has been proven as a promising therapeutic target for treating severe obesity syndrome. Numerous studies have demonstrated that central MC4R signaling is significantly affected by melanocortin receptor accessory protein 2 (MRAP2) in humans, mice and zebrafish. MRAP2 proteins exist as parallel or antiparallel dimers on the plasma membrane, but the structural insight of dual orientations with the pharmacological profiles has not yet been fully studied. Investigation and optimization of the conformational topology of MRAP2 are critical for the development of transmembrane allosteric modulators to treat MC4R-associated disorders. In this study, we synthesized a brand new single transmembrane protein by reversing wild-type mouse and zebrafish MRAP2 sequences and examined their dimerization, interaction and pharmacological activities on mouse and zebrafish MC4R signaling. We showed that the reversed zebrafish MRAPa exhibited an opposite function on modulating zMC4R signaling and the reversed mouse MRAP2 lost the capability for regulating MC4R trafficking but exhibited a novel function for cAMP cascades, despite proper expression and folding. Taken together, our results provided new biochemical insights on the oligomeric states and membrane orientations of MRAP2 proteins, as well as its pharmacological assistance for modulating MC4R signaling.

Achieving the efficacy and specificity of G-protein-coupled receptor (GPCR) targeting-drugs in the skin remains challenging. Understanding the molecular mechanism underlying GPCR dysfunction is crucial for developing targeted therapies. Recent advances in genetic, signal transduction, and structural studies have significantly improved our understanding of cutaneous GPCR functions in both normal and pathological states. In this review, we summarize recent discoveries of pathogenic GPCRs in dermal injuries, chronic inflammatory dermatoses, cutaneous malignancies, as well as the development of potent potential drugs. We also discuss targeting of cutaneous GPCR complexes via the transient receptor potential (TRP) channel and structure elucidation, which provide new opportunities for therapeutic targeting of GPCRs involved in skin disorders. These insights are expected to lead to more effective and specific treatments for various skin conditions.

Adrenal incidentalomas (AIs) are commonly detected endocrine lesions, identified during imaging for unrelated conditions. These lesions exhibit considerable heterogeneity and diverse clinical outcomes. This study employed single‐cell RNA sequencing to investigate tumorigenic characteristics of AIs, including non‐functional adrenocortical adenomas, Conn's syndrome, and pheochromocytomas. Through integrating public datasets, 302 696 cells are analyzed. Three adrenocortical cell subtypes exhibit gene expression patterns linked to tumorigenesis. Clusterin emerges as a potential biomarker for adrenocortical adenomas. Adrenocortical tumor cells show dysregulated hormone secretion and transcription factor steroidogenic factor 1 (SF1) is significantly upregulated, distinguishing cortical from medullary tumors. In pheochromocytomas, a MYCN proto‐oncogene (MYCN)‐positive cluster correlates with poorer survival. Immune microenvironment analysis reveals specific immune subtypes and roles in tumor progression. Specifically, myeloid cells may regulate benign tumors, while lymphoid cells, such as CD8‐positive (CD8+) T cells, appear to promote immune activation and infiltration in malignant tumors. Overall, this study enhances the understanding of adrenal adenoma heterogeneity, revealing crucial transcriptional profiles, immune interactions, and clinically relevant candidate biomarkers.

Recent progress in elucidating the role of specific antidiuretic hormones in Drosophila models has provided valuable insights into the mechanisms underlying tumor-induced renal dysfunction. Xu et al. identified the mammalian neurokinin 3 receptor (TACR3), a homolog of the G protein-coupled receptor TkR99D in fruit flies, as a potential therapeutic target for alleviating renal tubular dysfunction in mice with malignant neoplasms. Here, we commented on these findings by emphasizing the structural and evolutionary significance of TACR3 and provided an in-depth analysis of cell type specific expression of TACR3 in response to renal injury and expressional dynamics during renal carcinoma progression. The implications of these findings for transforming the therapeutic approaches to renal complications associated with oncological disorders were highlighted. We also acknowledged the limitations of current experimental models in this study and emphasized the necessary clinical validation in the future. These insights could contribute to the advancement of diagnostic and therapeutic strategies for treating tumor-related renal pathologies. Graphical Abstract