Chronic kidney disease is multifactorial and estimated to affect more than 840 million people worldwide constituting a major global health crisis. The number of patients will continue to rise mostly because of the aging population and the increased prevalence of comorbidities such as diabetes and hypertension. Patients with advanced stages display a loss of kidney function leading to an accumulation of, a.o. protein-bound uremic toxins that are poorly eliminated by renal replacement therapies. This systemic retention of toxic metabolites, known as the uremic syndrome, affects other organs. Indeed, neurological complications such as cognitive impairment, uremic encephalopathy, and anxiety have been reported in chronic kidney disease patients. Several factors are involved, including hemodynamic disorders and blood-brain barrier (BBB) impairment. The BBB guarantees the exchange of solutes between the blood and the brain through a complex cellular organization and a diverse range of transport proteins. We hypothesize that the increased exposure of the brain to protein-bound uremic toxins is involved in BBB disruption and induces a perturbation in the activity of endothelial membrane transporters. This phenomenon could play a part in the evolution of neurological disorders driven by this kidney-brain crosstalk impairment. In this review, we present chronic kidney disease-induced neurological complications by focusing on the pathological relationship between the BBB and protein-bound uremic toxins. The importance of mechanistically delineating the impact of protein-bound uremic toxins on BBB integrity and membrane drug transporter expression and function in brain endothelial capillary cells is highlighted. Additionally, we put forward current knowledge gaps in the literature.

Ischemia-reperfusion (IR)-induced acute kidney injury (IRI) is an inevitable event in kidney transplantation. It is a complex pathophysiological process associated with numerous structural and metabolic changes that have a profound influence on the early and the late function of the transplanted kidney. Proximal tubular cells are particularly sensitive to IRI. These cells are involved in renal and whole-body homeostasis, detoxification processes and drugs elimination by a transporter-dependent, transcellular transport system involving Solute Carriers (SLCs) and ATP Binding Cassettes (ABCs) transporters. Numerous studies conducted mainly in animal models suggested that IRI causes decreased expression and activity of some major tubular transporters. This could favor uremic toxins accumulation and renal metabolic alterations or impact the pharmacokinetic/toxicity of drugs used in transplantation. It is of particular importance to understand the underlying mechanisms and effects of IR on tubular transporters in order to improve the mechanistic understanding of IRI pathophysiology, identify biomarkers of graft function or promote the design and development of novel and effective therapies. Modulation of transporters’ activity could thus be a new therapeutic opportunity to attenuate kidney injury during IR.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with multidrug resistance (MDR) significantly limiting the effectiveness of chemotherapy. A major contributor to MDR is the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein ( ABCB1/P-gp), breast cancer resistance protein ( ABCG2/BCRP), and multidrug resistance-associated proteins ( ABCC/MRPs). These transporters actively efflux chemotherapeutic agents, reducing their intracellular drug accumulation and efficacy. This review outlines both clinical and emerging strategies that aim to overcome ABC transporter-mediated resistance in CRC. Herein, we detail the functional role of ABC transporters in CRC, followed by clinically tested approaches, such as pharmacological inhibitors, natural compound inhibitors, as well as nanoparticle-based drug delivery systems, that have been explored to circumvent resistance. In addition, we discuss emerging preclinical approaches, including CRISPR/Cas9 gene-editing, RNA interference, epigenetic modulators, and gut microbiome-targeted interventions, that hold promise for future therapeutic translation. By integrating clinically validated and experimental strategies, this review highlights the importance of a multimodal approach to effectively circumvent MDR in CRC and optimize personalized treatment strategies to improve clinical outcomes. ABC transporters; chemoresistance; colorectal cancer; multidrug resistance; therapies

Advances in pharmacomicrobiomics have shed light on the pathophysiology of drug‐induced enteropathy associated with the therapeutic use of certain non‐steroidal anti‐inflammatory drugs, anticancer chemotherapies and immunosuppressants. The toxicity pathway results from the post‐glucuronidation release and digestive accumulation of an aglycone generated in the context of intestinal dysbiosis characterized by the expansion of β‐glucuronidase‐expressing bacteria. The active aglycone could trigger direct or indirect inflammatory signaling on the gut epithelium. Therefore, taming bacterial β‐glucuronidase (GUS) activity is a druggable target for preventing drug‐induced enteropathy. In face of the limitations of antibiotic strategies that can worsen intestinal dysbiosis and impair immune functions, we hereby propose the use of a recombinant probiotic capable of mimicking repressive conditions of GUS through an inducible plasmid vector.

Membrane transporters play a central role in the absorption, distribution, metabolism, and elimination of drugs. Beyond drug handling, these transporters regulate the transport of endogenous metabolites, contributing to physiological homeostasis. Their activity is regulated not only by intrinsic cellular mechanisms but also by signals from distant organs. Understanding these processes is crucial for accurately predicting both local and systemic pharmacokinetics, as transporter function influences drug concentrations and effects at target tissues and throughout the organism. However, most current in vitro models do not recapitulate interorgan interactions or the dynamic regulation of transporter function. Microphysiological systems, particularly organ-on-chip, offer a promising approach to studying transporter biology in a more integrated and physiologically relevant context. This review provides an overview of the development and application of organ-on-chip technologies to investigate drug transporters and their regulation. Although significant technical progress has been made, these systems often remain focused on engineering or industrial goals, with limited impact on fundamental biological questions. Moreover, the high degree of customization and widespread use of homemade organ-on-chip models, with diverse materials, geometries, and cell sources, have created substantial barriers to reproducibility and cross-laboratory comparison. We here assess the current state of the field and identify gaps in modeling transporter regulation and interorgan communication. We also explore the potential of organ-on-chip to advance our understanding of systemic pharmacology. This review aims to reposition organ-on-chip platforms not only as technological demonstrators but also as experimental systems capable of generating new biological insights into transporter function and organ crosstalk. SIGNIFICANCE STATEMENT: Membrane transporters are central regulators of drug disposition and systemic homeostasis, yet their interorgan regulation remains poorly captured by conventional models. This review highlights how organ-on-chip technologies can bridge this gap, enabling mechanistic investigation of transporter function and advancing predictive, human-relevant pharmacology.

The human SLC22A6/OAT1 plays an important role in the elimination of a broad range of endogenous substances and xenobiotics thus attracting attention from the pharmacological community. Furthermore, OAT1 is also involved in key physiological events such as the remote inter-organ communication. Despite its significance, the knowledge about h OAT1 structure and the transport mechanism at the atomic level remains fragmented owing to the lack of resolved structures. By means of protein-threading modeling refined by μs-scaled Molecular Dynamics simulations, the present study provides the first robust model of h OAT1 in outward-facing conformation. Taking advantage of the AlphaFold 2 predicted structure of h OAT1 in inward-facing conformation, we here provide the essential structural and functional features comparing both states. The intracellular motifs conserved among Major Facilitator Superfamily members create a so-called “charge-relay system” that works as molecular switches modulating the conformation. The principal element of the event points at interactions of charged residues that appear crucial for the transporter dynamics and function. Moreover, h OAT1 model was embedded in different lipid bilayer membranes highlighting the crucial structural dependence on lipid-protein interactions. MD simulations supported the pivotal role of phosphatidylethanolamine components to the protein conformation stability. The present model is made available to decipher the impact of any observed polymorphism and mutation on drug transport as well as to understand substrate binding modes.