Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages.

Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2+ breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.

Chromatin Accessibility Landscape in Human Early Embryos and Its Association with Evolution.

The dynamics of the chromatin regulatory landscape during human early embryogenesis remains unknown. Using DNase I hypersensitive site (DHS) sequencing, we report that the chromatin accessibility landscape is gradually established during human early embryogenesis. Interestingly, the DHSs with OCT4 binding motifs are enriched at the timing of zygotic genome activation (ZGA) in humans, but not in mice. Consistently, OCT4 contributes to ZGA in humans, but not in mice. We further find that lower CpG promoters usually establish DHSs at later stages. Similarly, younger genes tend to establish promoter DHSs and are expressed at later embryonic stages, while older genes exhibit these features at earlier stages. Moreover, our data show that human active transposons SVA and HERV-K harbor DHSs and are highly expressed in early embryos, but not in differentiated tissues. In summary, our data provide an evolutionary developmental view for understanding the regulation of gene and transposon expression.

CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness.

Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.

3D Chromatin Structures of Mature Gametes and Structural Reprogramming during Mammalian Embryogenesis.

High-order chromatin structure plays important roles in gene expression regulation. Knowledge of the dynamics of 3D chromatin structures during mammalian embryo development remains limited. We report the 3D chromatin architecture of mouse gametes and early embryos using an optimized Hi-C method with low-cell samples. We find that mature oocytes at the metaphase II stage do not have topologically associated domains (TADs). In sperm, extra-long-range interactions (>4 Mb) and interchromosomal interactions occur frequently. The high-order structures of both the paternal and maternal genomes in zygotes and two-cell embryos are obscure but are gradually re-established through development. The establishment of the TAD structure requires DNA replication but not zygotic genome activation. Furthermore, unmethylated CpGs are enriched in A compartment, and methylation levels are decreased to a greater extent in A compartment than in B compartment in embryos. In summary, the global reprogramming of chromatin architecture occurs during early mammalian development.

NKILA lncRNA promotes tumor immune evasion by sensitizing T cells to activation-induced cell death.

Activation-induced cell death (AICD) of T lymphocytes can be exploited by cancers to escape immunological destruction. We demonstrated that tumor-specific cytotoxic T lymphocytes (CTLs) and type 1 helper T (TH1) cells, rather than type 2 helper T cells and regulatory T cells, were sensitive to AICD in breast and lung cancer microenvironments. NKILA, an NF-κB-interacting long noncoding RNA (lncRNA), regulates T cell sensitivity to AICD by inhibiting NF-κB activity. Mechanistically, calcium influx in stimulated T cells via T cell-receptor signaling activates calmodulin, thereby removing deacetylase from the NKILA promoter and enhancing STAT1-mediated transcription. Administering CTLs with NKILA knockdown effectively inhibited growth of breast cancer patient-derived xenografts in mice by increasing CTL infiltration. Clinically, NKILA overexpression in tumor-specific CTLs and TH1 cells correlated with their apoptosis and shorter patient survival. Our findings underscore the importance of lncRNAs in determining tumor-mediated T cell AICD and suggest that engineering lncRNAs in adoptively transferred T cells might provide a novel antitumor immunotherapy.

Programming and inheritance of parental DNA methylomes in mammals.

The reprogramming of parental methylomes is essential for embryonic development. In mammals, paternal 5-methylcytosines (5mCs) have been proposed to be actively converted to oxidized bases. These paternal oxidized bases and maternal 5mCs are believed to be passively diluted by cell divisions. By generating single-base resolution, allele-specific DNA methylomes from mouse gametes, early embryos, and primordial germ cell (PGC), as well as single-base-resolution maps of oxidized cytosine bases for early embryos, we report the existence of 5hmC and 5fC in both maternal and paternal genomes and find that 5mC or its oxidized derivatives, at the majority of demethylated CpGs, are converted to unmodified cytosines independent of passive dilution from gametes to four-cell embryos. Therefore, we conclude that paternal methylome and at least a significant proportion of maternal methylome go through active demethylation during embryonic development. Additionally, all the known imprinting control regions (ICRs) were classified into germ-line or somatic ICRs.

Sperm, but not oocyte, DNA methylome is inherited by zebrafish early embryos.

5-methylcytosine is a major epigenetic modification that is sometimes called "the fifth nucleotide." However, our knowledge of how offspring inherit the DNA methylome from parents is limited. We generated nine single-base resolution DNA methylomes, including zebrafish gametes and early embryos. The oocyte methylome is significantly hypomethylated compared to sperm. Strikingly, the paternal DNA methylation pattern is maintained throughout early embryogenesis. The maternal DNA methylation pattern is maintained until the 16-cell stage. Then, the oocyte methylome is gradually discarded through cell division and is progressively reprogrammed to a pattern similar to that of the sperm methylome. The passive demethylation rate and the de novo methylation rate are similar in the maternal DNA. By the midblastula stage, the embryo's methylome is virtually identical to the sperm methylome. Moreover, inheritance of the sperm methylome facilitates the epigenetic regulation of embryogenesis. Therefore, besides DNA sequences, sperm DNA methylome is also inherited in zebrafish early embryos.

Lactylation prediction models based on protein sequence and structural feature fusion.

Lysine lactylation (Kla) is a newly discovered posttranslational modification that is involved in important life activities, such as glycolysis-related cell function, macrophage polarization and nervous system regulation, and has received widespread attention due to the Warburg effect in tumor cells. In this work, we first design a natural language processing method to automatically extract the 3D structural features of Kla sites, avoiding potential biases caused by manually designed structural features. Then, we establish two Kla prediction frameworks, Attention-based feature fusion Kla model (ABFF-Kla) and EBFF-Kla, to integrate the sequence features and the structure features based on the attention layer and embedding layer, respectively. The results indicate that ABFF-Kla and Embedding-based feature fusion Kla model (EBFF-Kla), which fuse features from protein sequences and spatial structures, have better predictive performance than that of models that use only sequence features. Our work provides an approach for the automatic extraction of protein structural features, as well as a flexible framework for Kla prediction. The source code and the training data of the ABFF-Kla and the EBFF-Kla are publicly deposited at: https://github.com/ispotato/Lactylation_model.

DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25.

Neutrophil extracellular traps (NETs), which consist of chromatin DNA filaments coated with granule proteins, are released by neutrophils to trap microorganisms1-3. Recent studies have suggested that the DNA component of NETs (NET-DNA) is associated with cancer metastasis in mouse models4-6. However, the functional role and clinical importance of NET-DNA in metastasis in patients with cancer remain unclear. Here we show that NETs are abundant in the liver metastases of patients with breast and colon cancers, and that serum NETs can predict the occurrence of liver metastases in patients with early-stage breast cancer. NET-DNA acts as a chemotactic factor to attract cancer cells, rather than merely acting as a 'trap' for them; in several mouse models, NETs in the liver or lungs were found to attract cancer cells to form distant metastases. We identify the transmembrane protein CCDC25 as a NET-DNA receptor on cancer cells that senses extracellular DNA and subsequently activates the ILK-ß-parvin pathway to enhance cell motility. NET-mediated metastasis is abrogated in CCDC25-knockout cells. Clinically, we show that the expression of CCDC25 on primary cancer cells is closely associated with a poor prognosis for patients. Overall, we describe a transmembrane DNA receptor that mediates NET-dependent metastasis, and suggest that targeting CCDC25 could be an appealing therapeutic strategy for the prevention of cancer metastasis.

Hetero-Motif Molecular Junction Photocatalysts: A New Frontier in Artificial Photosynthesis.

ConspectusTo cope with the increasingly global greenhouse effect and energy shortage, it is urgent to develop a feasible means to convert anthropogenic excess carbon dioxide (CO2) into energy resources. The photocatalytic CO2 reduction reaction (CO2RR) coupled with the water oxidation reaction (WOR), known as artificial photosynthesis, is a green, clean, and promoting strategy to deal with the above issues. Among the reported photocatalytic systems for CO2 reduction, the main challenge is to achieve WOR simultaneously due to the limited charge separation efficiency and complicated dynamic process. To address the problem, scientists have assembled two nanosemiconductor motifs for CO2RR and WOR into a heterojunction photocatalyst to realize artificial photosynthesis. However, it is difficult to clearly explore the corresponding catalytic mechanism and establish an accurate structure-activity relationship at the molecular level for their aperiodic distribution and complicated structural information. Standing on the shoulders of the heterojunction photocatalysts, a new-generation material, hetero-motif molecular junction (HMMJ) photocatalysts, has been developed and studied by our laboratory. A hetero-motif molecular junction is a class of crystalline materials with a well-defined and periodic structure, adjustable assembly mode, and semiconductor-like properties, which is composed of two predesigned motifs with oxidation and reduction, respectively, by coordination or covalent bonds. The intrinsic properties make these catalysts susceptible to functional modifications to improve light absorption and electrical conductivity. The small size and short distance of the motifs can greatly promote the efficiency of photogenerated electron-hole separation and migration. Based on these advantages, they can be used as potential excellent photocatalysts for artificial photosynthesis. Notably, the explicit structural information determined by single-crystal or powder X-ray diffraction can provide a visual platform to explore the reaction mechanism. More importantly, the connection number, spatial distance, interaction, and arrangement mode of the structural motifs can be well-designed to explore the detailed structure-activity relationship that can be hardly studied in nanoheterojunction photocatalyst systems. In this regard, HMMJ photocatalysts can be a new frontier in artificial photosynthesis and serve as an important bridge between molecular photocatalysts and solid photocatalysts. Thus, it is very important to summarize the state-of-the-art of the HMMJ photocatalysts used for artificial photosynthesis and to give in-depth insight to promote future development.In this Account, we have summarized the recent advances in artificial photosynthesis using HMMJ photocatalysts, mainly focusing on the results in our lab. We present an overview of current knowledge about developed photocatalytic systems for artificial photosynthesis, introduce the design schemes of the HMMJ photocatalysts and their unique advantages as compared to other photocatalysts, summarize the construction strategies of HMMJ photocatalysts and their application in artificial photosynthesis, and explain why hetero-motif molecular junctions can be promising photocatalysts and show that they provide a powerful platform for studying photocatalysis. The structure-activity relationship and charge separation dynamics are illustrated. Finally, we bring our outlook on present challenges and future development of HMMJ photocatalysts and their potential application prospects on other photocatalytic reaction systems. We believe that this Account will afford important insights for the construction of high-efficiency photocatalysts and guidance for the development of more photocatalytic systems in an atom-economic, environmentally friendly, and sustainable way.

Key role for CTCF in establishing chromatin structure in human embryos.

In the interphase of the cell cycle, chromatin is arranged in a hierarchical structure within the nucleus1,2, which has an important role in regulating gene expression3-6. However, the dynamics of 3D chromatin structure during human embryogenesis remains unknown. Here we report that, unlike mouse sperm, human sperm cells do not express the chromatin regulator CTCF and their chromatin does not contain topologically associating domains (TADs). Following human fertilization, TAD structure is gradually established during embryonic development. In addition, A/B compartmentalization is lost in human embryos at the 2-cell stage and is re-established during embryogenesis. Notably, blocking zygotic genome activation (ZGA) can inhibit TAD establishment in human embryos but not in mouse or Drosophila. Of note, CTCF is expressed at very low levels before ZGA, and is then highly expressed at the ZGA stage when TADs are observed. TAD organization is significantly reduced in CTCF knockdown embryos, suggesting that TAD establishment during ZGA in human embryos requires CTCF expression. Our results indicate that CTCF has a key role in the establishment of 3D chromatin structure during human embryogenesis.

Molecular oxidation-reduction junctions for artificial photosynthetic overall reaction.

Constructing redox semiconductor heterojunction photocatalysts is the most effective and important means to complete the artificial photosynthetic overall reaction (i.e., coupling CO2 photoreduction and water photo-oxidation reactions). However, multiphase hybridization essence and inhomogeneous junction distribution in these catalysts extremely limit the diverse design and regulation of the modes of photogenerated charge separation and transfer pathways, which are crucial factors to improve photocatalytic performance. Here, we develop molecular oxidation-reduction (OR) junctions assembled with oxidative cluster (PMo12, for water oxidation) and reductive cluster (Ni5, for CO2 reduction) in a direct (d-OR), alternant (a-OR), or symmetric (s-OR) manner, respectively, for artificial photosynthesis. Significantly, the transfer direction and path of photogenerated charges between traditional junctions are obviously reformed and enriched in these well-defined crystalline catalysts with monophase periodic distribution and thus improve the separation efficiency of the electrons and holes. In particular, the charge migration in s-OR shows a periodically and continuously opposite mode. It can inhibit the photogenerated charge recombination more effectively and enhance the photocatalytic performance largely when compared with the traditional heterojunction models. Structural analysis and density functional theory calculations disclose that, through adjusting the spatial arrangement of oxidation and reduction clusters, the energy level and population of the orbitals of these OR junctions can be regulated synchronously to further optimize photocatalytic performance. The establishment of molecular OR junctions is a pioneering important discovery for extremely improving the utilization efficiency of photogenerated charges in the artificial photosynthesis overall reaction.

Global profiling of protein lactylation in Caenorhabditis elegans.

Lactylation, as a novel posttranslational modification, is essential for studying the functions and regulation of proteins in physiological and pathological processes, as well as for gaining in-depth knowledge on the occurrence and development of many diseases, including tumors. However, few studies have examined the protein lactylation of one whole organism. Thus, we studied the lactylation of global proteins in Caenorhabditis elegans to obtain an in vivo lactylome. Using an MS-based platform, we identified 1836 Class I (localization probabilities > 0.75) lactylated sites in 487 proteins. Bioinformatics analysis showed that lactylated proteins were mainly located in the cytoplasm and involved in the tricarboxylic acid cycle (TCA cycle) and other metabolic pathways. Then, we evaluated the conservation of lactylation in different organisms. In total, 41 C. elegans proteins were lactylated and homologous to lactylated proteins in humans and rats. Moreover, lactylation on H4K80 was conserved in three species. An additional 238 lactylated proteins were identified in C. elegans for the first time. This study establishes the first lactylome database in C. elegans and provides a basis for studying the role of lactylation.

FDA approval summary: fam-trastuzumab deruxtecan-nxki for unresectable or metastatic non-small cell lung cancer with activating HER2 mutations.

On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.

Proceedings of the 28th Annual Congress of the International Liver Transplantation Society.

The 2023 Joint International Congress of the International Liver Transplantation Society (ILTS), the European Liver and Intestine Transplant Association (ELITA), and the Liver Intensive Care Group of Europe (LICAGE) held in Rotterdam, the Netherlands, marked a significant recovery milestone for the liver transplant community after COVID-19. With 1159 participants and a surge in abstract submissions, the event focused on "Liver Disorders and Transplantation: Innovations and Evolving Indications." This conference report provides a comprehensive overview of the key themes discussed during the event, encompassing Hepatology, Anesthesia and Critical Care, Acute Liver Failure, Infectious Disease, Immunosuppression, Pediatric Liver Transplantation, Living Donor Liver Transplantation, Transplant Oncology, Surgical Approaches, and Machine Perfusion. The congress provided a platform for extensive discussions on a wide range of topics, reflecting the continuous advancements and collaborative efforts within the liver transplant community.

Improved photosynthetic performance under unilateral weak light conditions in a wide-narrow-row intercropping system is associated with altered sugar transport.

Intercropping improves resource utilization. Under wide-narrow-row maize (Zea mays) intercropping, maize plants are subjected to weak unilateral illumination and exhibit high photosynthetic performance. However, the mechanism regulating photosynthesis under unilateral weak light remains unknown. We investigated the relationship between photosynthesis and sugar metabolism in maize under unilateral weak light. Our results showed that the net photosynthetic rate (Pn) of unshaded leaves increased as the level of shade on the other side increased. On the contrary, the concentration of sucrose and starch and the number of starch granules in the unshaded leaves decreased with increased shading due to the transfer of abundant C into the grains. However, sink loss with ear removal reduced the Pn of unshaded leaves. Intense unilateral shade (40% to 20% normal light), but not mild unilateral shade (60% normal light), reduced grain yield (37.6% to 54.4%, respectively). We further found that in unshaded leaves, Agpsl, Bmy, and Mexl-like expression significantly influenced sucrose and starch metabolism, while Sweet13a and Sut1 expression was crucial for sugar export. In shaded leaves, expression of Sps1, Agpsl, and Sweet13c was crucial for sugar metabolism and export. This study confirmed that unshaded leaves transported photosynthates to the ear, leading to a decrease in sugar concentration. The improvement of photosynthetic performance was associated with altered sugar transport. We propose a narrow-row spacing of 40 cm, which provides appropriate unilateral shade and limits yield reduction.

A Simply Synthesized Shaking-induced Small Molecule System with Repeatableand Instantaneous Discoloration Response.

Force-related discoloration materials are highly valuable because of their characteristics of visualization, easy operation, and environment friendliness. Most force-related discoloration materials focus on polymers and depend on bond scission, which leads to insensitivity and unrecoverable. Small-molecule systems based on well-defined molecular structures and simple composition with high sensitivity would exhibit considerable mechanochromic potential. However, to date, researches about force-related discoloration materials based on small molecule solution remain limited and are rarely reported. In this study, we developed a repeatable and instantaneous discoloration small molecule solution system by simple one-pot synthesis method. It exhibited an instantaneous chromic change from yellowish to dark green under shaking and reverting back to yellow within 1 minute after removal of the shaking. Experimental results confirmed that the discoloration mechanism is attributed to the oscillation accelerating the production of unstable ortho-OH phenoxyl radical. The newly developed shaking-induced discoloration small molecule system (SDSMS) promises in field of mechanical force sensing and optical encryption.

UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.

Ubiquitin fold modifier 1 is a small ubiquitin-like protein modifier that is essential for embryonic development of metazoans. Although UFMylation has been connected to endoplasmic reticulum homeostasis, the underlying mechanisms and the relevant cellular targets are largely unknown. Here, we show that HRD1, a ubiquitin ligase of ER-associated protein degradation (ERAD), is a novel substrate of UFM1 conjugation. HRD1 interacts with UFMylation components UFL1 and DDRGK1 and is UFMylated at Lys610 residue. In UFL1-depleted cells, the stability of HRD1 is increased and its ubiquitination modification is reduced. In the event of ER stress, the UFMylation and ubiquitination modification of HRD1 is gradually inhibited over time. Alteration of HRD1 Lys610 residue to arginine impairs its ability to degrade unfolded or misfolded proteins to disturb protein processing in ER. These results suggest that UFMylation of HRD1 facilitates ERAD function to maintain ER homeostasis.

Na/K-ATPase signaling tonically inhibits sodium reabsorption in the renal proximal tubule.

Through its classic ATP-dependent ion-pumping function, basolateral Na/K-ATPase (NKA) generates the Na+ gradient that drives apical Na+ reabsorption in the renal proximal tubule (RPT), primarily through the Na+ /H+ exchanger (NHE3). Accordingly, activation of NKA-mediated ion transport decreases natriuresis through activation of basolateral (NKA) and apical (NHE3) Na+ reabsorption. In contrast, activation of the more recently discovered NKA signaling function triggers cellular redistribution of RPT NKA and NHE3 and decreases Na+ reabsorption. We used gene targeting to test the respective contributions of NKA signaling and ion pumping to the overall regulation of RPT Na+ reabsorption. Knockdown of RPT NKA in cells and mice increased membrane NHE3 and Na+ /HCO3 - cotransporter (NBCe1A). Urine output and absolute Na+ excretion decreased by 65%, driven by increased RPT Na+ reabsorption (as indicated by decreased lithium clearance and unchanged glomerular filtration rate), and accompanied by elevated blood pressure. This hyper reabsorptive phenotype was rescued upon crossing with RPT NHE3-/- mice, confirming the importance of NKA/NHE3 coupling. Hence, NKA signaling exerts a tonic inhibition on Na+ reabsorption by regulating key apical and basolateral Na+ transporters. This action, lifted upon NKA genetic suppression, tonically counteracts NKA's ATP-driven function of basolateral Na+ reabsorption. Strikingly, NKA signaling is not only physiologically relevant but it also appears to be functionally dominant over NKA ion pumping in the control of RPT reabsorption.

An optimized short-term steroid therapy for chronic drug-induced liver injury: A prospective randomized clinical trial.

BACKGROUND AND AIMS: The use of corticosteroids in chronic drug-induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48-week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36-week SSR can achieve efficacy similar to that of 48-week SSR. METHODS: A randomized open-label trial was performed. Eligible patients were randomly assigned to the 36- or 48-week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety. RESULTS: Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36-week SSR group but 4.8% in the 48-week SSR group, as determined by per-protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p = .701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed. CONCLUSIONS: Both the 36- and 48-week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36-week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146).