Livers

Androgen receptor (AR) signaling has a pivotal role in hepatic lipid homeostasis, as well as in core metabolic functions such as lipogenesis, fatty acid oxidation, and insulin sensitivity. Dysregulation of AR function has been demonstrated in both animal and human studies to disrupt these crucial metabolic pathways, thereby promoting hepatic steatosis. Several causes can lead to AR dysregulation, including genetic mutations or polymorphisms, epigenetic and post-transcriptional modifications, as well as various endocrine disturbances. Prompted by a diagnostically challenging case of a lean 34-year-old male with persistent ALT-predominant transaminasemia, unexplained suboptimal dyslipidemia despite adherence to drug therapy and a healthy lifestyle, and chronically elevated creatine phosphokinase levels irrespective of statin use or exercise intensity, we highlight the overlooked mechanistic link between AR dysfunction and liver–muscle disruption in lean-MASLD patients. Considering the pivotal role of AR in liver–muscle crosstalk, we emphasize the importance of evaluating AR signaling pathways through targeted genetic testing in cases of lean-MASLD among the male population, as well as addressing other extrahepatic manifestations, such as neuromuscular diseases, closely related to AR dysfunction. This clinical strategy may ultimately optimize lean-MASLD management, particularly in view of the emerging utilization of AR-targeted therapeutic modalities, and may also facilitate the management of systemic manifestations associated with altered AR signaling pathways.

Background: Surgical resection (SR) and liver transplantation (LT) are the main curative options for non-hepatocellular carcinoma (non-HCC) liver malignancies, including colorectal liver metastases (CRLMs), intrahepatic cholangiocarcinoma (iCCA), hilar cholangiocarcinoma (hCCA), and neuroendocrine tumor liver metastases (NETLMs). Resection aims for negative margins and adequate hepatic reserve, while LT offers treatment for unresectable disease but is limited by donor scarcity, immunosuppression, and ethical constraints. Methods: A targeted literature search (2005–2025) was conducted using PubMed and Google Scholar with predefined MeSH terms combining “liver resection,” “hepatectomy,” and “liver transplantation” across non-HCC malignancies. Relevant studies, reviews, and guidelines were included. Results: For CRLMs, SR remains standard with 5-year overall survival (OS) up to 58%, while LT offers 60–83% in highly selected unresectable cases. In iCCA, resection achieves median survival around 40 months, and LT yields OS up to 69% in very early or neoadjuvant-controlled disease. For hCCA, the Mayo protocol combining neoadjuvant therapy with LT provides 5-year OS of 65–80%. In NETLMs, LT achieves 63–97% OS under strict criteria. Conclusions: SR remains first-line for resectable non-HCC malignancies, while LT provides superior outcomes in unresectable yet biologically favorable disease, emphasizing careful selection and organ allocation.

Background: Liver fibrosis is a progressive pathological condition characterized by excessive extracellular matrix deposition, driven by activated hepatic stellate cells (aHSCs). Effective therapeutic strategies require targeting aHSCs and agents capable of reversing their activated phenotype. Methods: In this study, we developed chitosan nanoparticles loaded with atorvastatin (AS) and JQ1 and functionalized them with varying densities of retinol (Rt) to exploit aHSC targeting. Results: In vitro, Rt-NPs demonstrated enhanced uptake in GRX cells, with optimal performance observed at high Rt density (HRt-NPs). In vivo biodistribution in CCl₄-induced fibrotic and healthy mice revealed that LRt-NPs achieved superior hepatic accumulation in fibrotic livers compared to unmodified and HRt-NPs, underscoring the importance of optimal ligand density for targeting. Western blot analysis showed that treatment of GRX cells with Rt-AS-NPs and Rt-JQ1-NPs either individually or combined significantly reduced the expression of fibronectin, vimentin, and PDGFR-β, key markers of HSC activation, with combination therapy providing more significant effects. Conclusions: This work highlights the potential of Rt-chitosan NPs loaded with AS and JQ1 as an effective dual-drug system for targeted antifibrotic therapy, offering enhanced hepatic selectivity, improved safety, and potent aHSC deactivation.