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SJTU Secures Another Nature Publication: Ruijin Hospital Team Achieves Major Breakthrough

March 01, 2026 Page views: 92

SJTU Secures Another Nature Publication: Ruijin Hospital Team Achieves Major Breakthrough

On January 28, 2026 (local time), Xu Huaqiang, researcher at the Center for Structural Biology and Drug Discovery of Ruijin Hospital affiliated with the Shanghai Jiao Tong University School of Medicine and the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, together with collaborators, published a research article entitled “Structures of Ostα-β reveal a unique fold and bile acid transport mechanism” in Nature. By comprehensively integrating cryo-electron microscopy structural determination, molecular dynamics simulations, and electrophysiological functional analyses, the study systematically elucidated the unique three-dimensional conformation of Ostα/β, its substrate recognition pattern, and its transmembrane transport mechanism. The findings provide critical evidence for resolving this long-standing mechanistic question.

Original article link: https://www.nature.com/articles/s41586-025-10029-7

Bile acids play a vital role in the human body, functioning as true “multitaskers.” They are indispensable in the digestion and absorption of nutrients, the regulation of energy metabolism, and the maintenance of hormonal signaling homeostasis. Bile acids continuously circulate between the liver and the intestine, forming the highly coordinated enterohepatic circulation, which relies on the concerted action of multiple membrane transporters. The proper operation of this cycle depends on a series of “transport assistants,” namely membrane transporters, each performing distinct yet coordinated roles to ensure the efficient bidirectional movement of bile acids. Over the past several decades, most of the transporters involved in this process have been identified and their mechanistic frameworks relatively well characterized. However, one critical question has remained unresolved: how are bile acids efficiently exported from the basolateral membrane of enterocytes into the portal circulation to sustain the cycle?

We may first consider the classical model governing bile acid transport in the liver. At the sinusoidal membrane—functionally equivalent to the “front door” of hepatocytes—bile acids are taken up via sodium-dependent or facilitated transporters. At the canalicular membrane—the “back door” of hepatocytes—ATP-binding cassette (ABC) transporters actively export bile acids in an energy-dependent manner. It was long hypothesized that a similar “input–output” logic might also operate in other epithelial tissues, including the intestine. However, the discovery in 2004 of the organic solute transporter Ostα/β challenged this assumption. Rather than functioning as a single “assistant,” this transporter exists as a heterodimer composed of Ostα and Ostβ subunits. Subsequent studies confirmed that it serves as the principal efflux mediator for bile acids at the basolateral membrane of enterocytes (as shown in Fig. 1A, B). Nevertheless, the precise mechanism by which it operates has remained elusive.

Figure 1. Schematic representation of the assembly and overall structure of the human Ostα/β tetramer

This study systematically elucidates the structural basis and working mechanism of Ostα/β at both structural and functional levels. At atomic resolution, it fills the long-missing key link in bile acid efflux within the enterohepatic circulation, providing a definitive answer to a long-standing challenge in the field and offering important insights for the precise therapeutic intervention of related diseases.

Disorders of bile acid metabolism constitute an important pathological basis for a range of hepatobiliary diseases, including cholestasis and non-alcoholic fatty liver disease. The in-depth elucidation of the structure and transport mechanism of Ostα/β establishes it, for the first time, as a potential therapeutic target with a clearly defined structural framework and regulatory mechanism. From a translational perspective, targeted modulation of the transport activity or directionality of Ostα/β may enable precise regulation of bile acid distribution between the liver and intestine under different pathological conditions. Such an approach holds promise for alleviating cholestasis, reducing bile acid–mediated hepatocellular toxicity, and improving associated metabolic abnormalities. This advancement shifts therapeutic strategies for bile acid–related diseases from the traditional paradigm of “indirect metabolic pathway modulation” toward a more precise strategy of “direct intervention at key transport steps,” representing a fundamentally new treatment concept.

In addition, comparative structural analyses revealed that Ostα/β shares significant topological similarity with the TMEM184 protein family, whose functions remain incompletely characterized. This finding suggests that members of the TMEM184 family may belong to a novel class of transporters rather than functioning as conventional membrane receptors, as previously assumed. The discovery opens new avenues for re-evaluating the biological roles of the TMEM184 family and exploring their potential associations with disease.

In this study, the team successfully expressed and purified the human Ostα/β complex in mammalian cells and subsequently determined its structure at a resolution of 2.6–3.1 Å using single-particle cryo-electron microscopy (Fig. 1C). Structural analysis revealed that Ostα/β does not exist as isolated units but assembles into a symmetric tetramer, composed of two Ostα–Ostβ heterodimers (Fig. 1D, E). Notably, the Ostα subunit adopts a previously uncharacterized seven-transmembrane helical fold (Fig. 1F), which exhibits no significant homology to any known transporter family. The Ostβ subunit contributes a single transmembrane helix positioned adjacent to the seventh transmembrane helix of Ostα, stabilizing the core architecture of the complex in a “side-by-side” manner. This unique structural organization explains why Ostα/β is classified independently as the SLC51 protein family.

Figure 2. The lateral substrate-binding pocket and translocation pathway of Ostα/β

Further structural analysis revealed the presence of a laterally open substrate-binding groove within the membrane region proximal to the cytoplasmic side. This groove is formed by a cysteine-rich intracellular loop that undergoes extensive palmitoylation (Fig. 2A, C). Such distinctive lipid modifications, together with surrounding hydrophobic amino acids, create a localized microenvironment well suited for the binding of amphipathic steroid molecules. The research team successfully resolved high-resolution complex structures of Ostα/β bound to two physiological substrates—taurolithocholic acid (TLCA) (Fig. 2B) and dehydroepiandrosterone sulfate (DHEAS). The structures clearly demonstrate that positively charged arginine residues (R241 and R244) within the groove form specific electrostatic interactions with the sulfate groups of the substrates, thereby conferring selectivity toward negatively charged molecules. Beyond the static substrate-binding site, integration of three-dimensional reconstruction density maps and structural analyses identified a hydrophilic channel extending from the basal binding groove toward the extracellular side (Fig. 2D). Combined with molecular dynamics simulations, the study proposes that substrates may undergo transmembrane translocation through this channel.

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Figure 3. Voltage-dependent transport by Ostα/β

Structural analysis and mechanistic hypotheses alone were not sufficient. To directly validate the transport process, the research team performed dynamic functional experiments. For the first time, they exploited the charged nature of bile acid derivatives and employed whole-cell patch-clamp recordings in cells expressing Ostα/β, directly measuring membrane potential–dependent transmembrane currents triggered by substrate (DHEAS) application (Fig. 3). This approach converts the transport of bile acids into detectable electrical signals, enabling real-time and controllable observation of the process. The experiments confirmed that Ostα/β functions as a facilitated diffusion carrier whose transport direction is not fixed, but rather determined by the combined electrochemical gradients of the substrate across the membrane. Specifically, membrane potential acts as a key regulatory factor that can “bias” the direction of transport: depolarization favors substrate influx, whereas hyperpolarization promotes substrate efflux. Thus, membrane potential is not merely a passive background parameter, but a critical determinant that biases bidirectional transport, enabling Ostα/β to preferentially support bile acid efflux under different physiological conditions.

Professor Ma Xiong of Renji Hospital, affiliated with the Shanghai Jiao Tong University School of Medicine, served as a co-corresponding author of the study. Dr. Yang Xuemei, postdoctoral researcher at the Center for Structural Biology and Drug Discovery of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Dr. Cui Nana, postdoctoral researcher at Renji Hospital, Shanghai Jiao Tong University School of Medicine; Li Tianyu, Assistant Researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences; and He Xinheng, a Ph.D. graduate of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, are co–first authors of the paper.