m6A-modified cenRNA stabilizes CENPA to ensure centromere integrity in cancer cells.

m6A modification is best known for its critical role in controlling multiple post-transcriptional processes of the mRNAs. Here, we discovered elevated levels of m6A modification on centromeric RNA (cenRNA) in cancerous cells compared with non-cancerous cells. We then identified CENPA, an H3 variant, as an m6A reader of cenRNA. CENPA is localized at centromeres and is essential in preserving centromere integrity and function during mitosis. The m6A-modified cenRNA stabilizes centromeric localization of CENPA in cancer cells during the S phase of the cell cycle. Mutations of CENPA at the Leu61 and the Arg63 or removal of cenRNA m6A modification lead to loss of centromere-bound CENPA during S phase. This in turn results in compromised centromere integrity and abnormal chromosome separation and hinders cancer cell proliferation and tumor growth. Our findings unveil an m6A reading mechanism by CENPA that epigenetically governs centromere integrity in cancer cells, providing potential targets for cancer therapy.

Algorithm for optimized mRNA design improves stability and immunogenicity.

Messenger RNA (mRNA) vaccines are being used to combat the spread of COVID-19 (refs. 1-3), but they still exhibit critical limitations caused by mRNA instability and degradation, which are major obstacles for the storage, distribution and efficacy of the vaccine products4. Increasing secondary structure lengthens mRNA half-life, which, together with optimal codons, improves protein expression5. Therefore, a principled mRNA design algorithm must optimize both structural stability and codon usage. However, owing to synonymous codons, the mRNA design space is prohibitively large-for example, there are around 2.4 × 10632 candidate mRNA sequences for the SARS-CoV-2 spike protein. This poses insurmountable computational challenges. Here we provide a simple and unexpected solution using the classical concept of lattice parsing in computational linguistics, where finding the optimal mRNA sequence is analogous to identifying the most likely sentence among similar-sounding alternatives6. Our algorithm LinearDesign finds an optimal mRNA design for the spike protein in just 11 minutes, and can concurrently optimize stability and codon usage. LinearDesign substantially improves mRNA half-life and protein expression, and profoundly increases antibody titre by up to 128 times in mice compared to the codon-optimization benchmark on mRNA vaccines for COVID-19 and varicella-zoster virus. This result reveals the great potential of principled mRNA design and enables the exploration of previously unreachable but highly stable and efficient designs. Our work is a timely tool for vaccines and other mRNA-based medicines encoding therapeutic proteins such as monoclonal antibodies and anti-cancer drugs7,8.

CXCR4/CXCL12 mediate autocrine cell- cycle progression in NF1-associated malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell-cycle progression through PI3-kinase (PI3K) and ß-catenin signaling. Suppression of CXCR4 activity either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development and identify a therapeutic target.

An updated model of shoot apical meristem regulation by ERECTA family and CLAVATA3 signaling pathways in Arabidopsis.

The shoot apical meristem (SAM) gives rise to the aboveground organs of plants. The size of the SAM is relatively constant due to the balance between stem cell replenishment and cell recruitment into new organs. In angiosperms, the transcription factor WUSCHEL (WUS) promotes stem cell proliferation in the central zone of the SAM. WUS forms a negative feedback loop with a signaling pathway activated by CLAVATA3 (CLV3). In the periphery of the SAM, the ERECTA family receptors (ERfs) constrain WUS and CLV3 expression. Here, we show that four ligands of ERfs redundantly inhibit the expression of these two genes. Transcriptome analysis confirmed that WUS and CLV3 are the main targets of ERf signaling and uncovered new ones. Analysis of promoter reporters indicated that the WUS expression domain mostly overlaps with the CLV3 domain and does not shift along the apical-basal axis in clv3 mutants. Our three-dimensional mathematical model captured gene expression distributions at the single-cell level under various perturbed conditions. Based on our findings, CLV3 regulates cellular levels of WUS mostly through autocrine signaling, and ERfs regulate the spatial expression of WUS, preventing its encroachment into the peripheral zone.

The phosphatidylethanolamine-binding proteins OsMFT1 and OsMFT2 regulate seed dormancy in rice.

Seed dormancy is crucial for optimal plant life-cycle timing. However, domestication has largely diminished seed dormancy in modern cereal cultivars, leading to challenges such as preharvest sprouting (PHS) and subsequent declines in yield and quality. Therefore, it is imperative to unravel the molecular mechanisms governing seed dormancy for the development of PHS-resistant varieties. In this study, we screened a mutant of BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR4 (OsbHLH004) with decreased seed dormancy and revealed that OsbHLH004 directly regulates the expression of 9-CIS-EPOXYCAROTENOID DIOXYGENASE3 (OsNCED3) and GIBBERELLIN 2-OXIDASE6 (OsGA2ox6) in rice (Oryza sativa). Additionally, we determined that two phosphatidylethanolamine-binding proteins, MOTHER OF FT AND TFL1 and 2 (OsMFT1 and OsMFT2; hereafter OsMFT1/2) interact with OsbHLH004 and Ideal Plant Architecture 1 (IPA1) to regulate their binding capacities on OsNCED3 and OsGA2ox6, thereby promoting seed dormancy. Intriguingly, FT-INTERACTING PROTEIN1 (OsFTIP1) interacts with OsMFT1/2 and affects their nucleocytoplasmic translocation into the nucleus, where OsMFT1/2-OsbHLH004 and OsMFT1/2-IPA1 antagonistically modulate the expression of OsNCED3 and OsGA2ox6. Our findings reveal that OsFTIP1-mediated inhibition of nuclear translocation of OsMFT1/2 and the dynamic transcriptional modulation of OsNCED3 and OsGA2ox6 by OsMFT1/2-OsbHLH004 and OsMFT1/2-IPA1 complexes in seed dormancy in rice.

Goal-directed attention transforms both working and long-term memory representations in the human parietal cortex.

The abundance of distractors in the world poses a major challenge to our brain's limited processing capacity, but little is known about how selective attention modulates stimulus representations in the brain to reduce interference and support durable target memory. Here, we collected functional magnetic resonance imaging (fMRI) data in a selective attention task in which target and distractor pictures of different visual categories were simultaneously presented. Participants were asked to selectively process the target according to the effective cue, either before the encoding period (i.e., perceptual attention) or the maintenance period (i.e., reflective attention). On the next day, participants were asked to perform a memory recognition task in the scanner in which the targets, distractors, and novel items were presented in a pseudorandom order. Behavioral results showed that perceptual attention was better at enhancing target memory and reducing distractor memory than reflective attention, although the overall memory capacity (memory for both target and distractor) was comparable. Using multiple-voxel pattern analysis of the neural data, we found more robust target representation and weaker distractor representation in working memory for perceptual attention than for reflective attention. Interestingly, perceptual attention partially shifted the regions involved in maintaining the target representation from the visual cortex to the parietal cortex. Furthermore, the targets and distractors simultaneously presented in the perceptual attention condition showed reduced pattern similarity in the parietal cortex during retrieval compared to items not presented together. This neural pattern repulsion positively correlated with individuals' recognition of both targets and distractors. These results emphasize the critical role of selective attention in transforming memory representations to reduce interference and improve long-term memory performance.

Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration.

Stroma in the tumor microenvironment plays a critical role in cancer progression, but how it promotes metastasis is poorly understood. Exosomes are small vesicles secreted by many cell types and enable a potent mode of intercellular communication. Here, we report that fibroblast-secreted exosomes promote breast cancer cell (BCC) protrusive activity and motility via Wnt-planar cell polarity (PCP) signaling. We show that exosome-stimulated BCC protrusions display mutually exclusive localization of the core PCP complexes, Fzd-Dvl and Vangl-Pk. In orthotopic mouse models of breast cancer, coinjection of BCCs with fibroblasts dramatically enhances metastasis that is dependent on PCP signaling in BCCs and the exosome component, Cd81 in fibroblasts. Moreover, we demonstrate that trafficking in BCCs promotes tethering of autocrine Wnt11 to fibroblast-derived exosomes. This work reveals an intercellular communication pathway whereby fibroblast exosomes mobilize autocrine Wnt-PCP signaling to drive BCC invasive behavior.

Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome.

The study of 5-hydroxylmethylcytosines (5hmC) has been hampered by the lack of a method to map it at single-base resolution on a genome-wide scale. Affinity purification-based methods cannot precisely locate 5hmC nor accurately determine its relative abundance at each modified site. We here present a genome-wide approach, Tet-assisted bisulfite sequencing (TAB-Seq), that when combined with traditional bisulfite sequencing can be used for mapping 5hmC at base resolution and quantifying the relative abundance of 5hmC as well as 5mC. Application of this method to embryonic stem cells not only confirms widespread distribution of 5hmC in the mammalian genome but also reveals sequence bias and strand asymmetry at 5hmC sites. We observe high levels of 5hmC and reciprocally low levels of 5mC near but not on transcription factor-binding sites. Additionally, the relative abundance of 5hmC varies significantly among distinct functional sequence elements, suggesting different mechanisms for 5hmC deposition and maintenance.

An integrated space-to-ground quantum communication network over 4,600 kilometres.

Quantum key distribution (QKD)1,2 has the potential to enable secure communication and information transfer3. In the laboratory, the feasibility of point-to-point QKD is evident from the early proof-of-concept demonstration in the laboratory over 32 centimetres4; this distance was later extended to the 100-kilometre scale5,6 with decoy-state QKD and more recently to the 500-kilometre scale7-10 with measurement-device-independent QKD. Several small-scale QKD networks have also been tested outside the laboratory11-14. However, a global QKD network requires a practically (not just theoretically) secure and reliable QKD network that can be used by a large number of users distributed over a wide area15. Quantum repeaters16,17 could in principle provide a viable option for such a global network, but they cannot be deployed using current technology18. Here we demonstrate an integrated space-to-ground quantum communication network that combines a large-scale fibre network of more than 700 fibre QKD links and two high-speed satellite-to-ground free-space QKD links. Using a trusted relay structure, the fibre network on the ground covers more than 2,000 kilometres, provides practical security against the imperfections of realistic devices, and maintains long-term reliability and stability. The satellite-to-ground QKD achieves an average secret-key rate of 47.8 kilobits per second for a typical satellite pass-more than 40 times higher than achieved previously. Moreover, its channel loss is comparable to that between a geostationary satellite and the ground, making the construction of more versatile and ultralong quantum links via geosynchronous satellites feasible. Finally, by integrating the fibre and free-space QKD links, the QKD network is extended to a remote node more than 2,600 kilometres away, enabling any user in the network to communicate with any other, up to a total distance of 4,600 kilometres.

Phosphorescent metallaknots of Au(I)-bis(acetylide) strands directed by Cu(I) π-coordination.

Knots containing metal atoms as part of their continuous strand backbone are termed as metallaknots. While several metallaknots have been synthesized through one-pot self-assembly, the designed synthesis of metallaknots by controlling the arrangement of entanglements and strands connectivity remains unexplored. Here, we report the synthesis of metallaknots composed with Au(I)-bis(acetylide) linkages and templated by Cu(I) ions. Varying the ratio of the building blocks results in the switchable formation of two trefoil knots with different stoichiometries and symmetries (C2 or D3) and an entangled metalla-complex. While the entangled complex formed serendipitously, the strand ends can be subsequently linked through coordinative closure to generate a 41 metallaknot in a highly designable fashion. The comparable structural characteristics of resulting metalla-complexes allow us to probe the correlations between their topologies and photophysical properties, showing the backbone rigidity of knots endows complexes with excellent phosphorescent properties. This strategy, in conjunction with the coordinative closure approach, provides a straightforward route for the formation of highly phosphorescent metallaknots that were previously challenging to access.

Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence.

Bacterial persister cells, a sub-population of dormant phenotypic variants highly tolerant to antibiotics, present a significant challenge for infection control. Investigating the mechanisms of antibiotic persistence is crucial for developing effective treatment strategies. Here, we found a significant association between tolerance frequency and previous infection history in bovine mastitis. Previous S. aureus infection led to S. aureus tolerance to killing by rifampicin in subsequent infection in vivo and in vitro. Actually, the activation of trained immunity contributed to rifampicin persistence of S. aureus in secondary infection, where it reduced the effectiveness of antibiotic treatment and increased disease severity. Mechanically, we found that S. aureus persistence was mediated by the accumulation of fumarate provoked by trained immunity. Combination therapy with metformin and rifampicin promoted eradication of persisters and improved the severity of recurrent S. aureus infection. These findings provide mechanistic insight into the relationship between trained immunity and S. aureus persistence, while providing proof of concept that trained immunity is a therapeutic target in recurrent bacterial infections involving persistent pathogens.

Entanglement-based secure quantum cryptography over 1,120 kilometres.

Quantum key distribution (QKD)1-3 is a theoretically secure way of sharing secret keys between remote users. It has been demonstrated in a laboratory over a coiled optical fibre up to 404 kilometres long4-7. In the field, point-to-point QKD has been achieved from a satellite to a ground station up to 1,200 kilometres away8-10. However, real-world QKD-based cryptography targets physically separated users on the Earth, for which the maximum distance has been about 100 kilometres11,12. The use of trusted relays can extend these distances from across a typical metropolitan area13-16 to intercity17 and even intercontinental distances18. However, relays pose security risks, which can be avoided by using entanglement-based QKD, which has inherent source-independent security19,20. Long-distance entanglement distribution can be realized using quantum repeaters21, but the related technology is still immature for practical implementations22. The obvious alternative for extending the range of quantum communication without compromising its security is satellite-based QKD, but so far satellite-based entanglement distribution has not been efficient23 enough to support QKD. Here we demonstrate entanglement-based QKD between two ground stations separated by 1,120 kilometres at a finite secret-key rate of 0.12 bits per second, without the need for trusted relays. Entangled photon pairs were distributed via two bidirectional downlinks from the Micius satellite to two ground observatories in Delingha and Nanshan in China. The development of a high-efficiency telescope and follow-up optics crucially improved the link efficiency. The generated keys are secure for realistic devices, because our ground receivers were carefully designed to guarantee fair sampling and immunity to all known side channels24,25. Our method not only increases the secure distance on the ground tenfold but also increases the practical security of QKD to an unprecedented level.

Molecular basis of an atypical dsDNA 5mC/6mA bifunctional dioxygenase CcTet from Coprinopsis cinerea in catalyzing dsDNA 5mC demethylation.

The eukaryotic epigenetic modifications 5-methyldeoxycytosine (5mC) and N6-methyldeoxyadenine (6mA) have indispensable regulatory roles in gene expression and embryonic development. We recently identified an atypical bifunctional dioxygenase CcTet from Coprinopsis cinerea that works on both 5mC and 6mA demethylation. The nonconserved residues Gly331 and Asp337 of CcTet facilitate 6mA accommodation, while D337F unexpectedly abolishes 5mC oxidation activity without interfering 6mA demethylation, indicating a prominent distinct but unclear 5mC oxidation mechanism to the conventional Tet enzymes. Here, we assessed the molecular mechanism of CcTet in catalyzing 5mC oxidation by representing the crystal structure of CcTet-5mC-dsDNA complex. We identified the distinct mechanism by which CcTet recognizes 5mC-dsDNA compared to 6mA-dsDNA substrate. Moreover, Asp337 was found to have a central role in compensating for the loss of a critical 5mC-stablizing H-bond observed in conventional Tet enzymes, and stabilizes 5mC and subsequent intermediates through an H-bond with the N4 atom of the substrates. These findings improve our understanding of Tet enzyme functions in the dsDNA 5mC and 6mA demethylation pathways, and provide useful information for future discovery of small molecular probes targeting Tet enzymes in DNA active demethylation processes.

Intersubject similarity in neural representations underlies shared episodic memory content.

Individuals generally form their unique memories from shared experiences, yet the neural representational mechanisms underlying this subjectiveness of memory are poorly understood. The current study addressed this important question from the cross-subject neural representational perspective, leveraging a large functional magnetic resonance imaging dataset (n = 415) of a face-name associative memory task. We found that individuals' memory abilities were predicted by their synchronization to the group-averaged, canonical trial-by-trial activation level and, to a lesser degree, by their similarity to the group-averaged representational patterns during encoding. More importantly, the memory content shared between pairs of participants could be predicted by their shared local neural activation pattern, particularly in the angular gyrus and ventromedial prefrontal cortex, even after controlling for differences in memory abilities. These results uncover neural representational mechanisms for individualized memory and underscore the constructive nature of episodic memory.

A spin-mechanical quantum chip for exploring exotic interactions.

How to illuminate dark matter has become the foremost open question in fundamental science nowadays, which is of great significance in understanding the laws of nature. Exploring exotic interactions beyond the standard model is one of the essential approaches to searching for dark matter particles. Although it has been explored in a variety of lab-scale and tabletop-scale setups over the past years, no such interactions have been observed, and improving the sensitivity significantly becomes of paramount importance, but challenging. Here, we formulate the conception of a spin-mechanical quantum chip compatible with scalable on-chip detectors. Utilizing the prototype chip realized by the integration of a mechanical resonator and a diamond with single nitrogen vacancy at the microscale, the constraints of spin-velocity-dependent interactions have been improved by two orders of magnitude, where there is no evidence for new bosons in the force range below 100 nm, i.e., in the rest-mass window of 2-10 electronvolts. Based on the proof-of-principle experiment, this promising chip can be scaled up to meet the requirements of searching for exotic interactions at preeminent sensitivity. Low-cost and high-yield chip-scale setups will accelerate the process of dark matter exploration, providing a path toward on-chip fundamental physics experiments.

BAPID suppresses the inhibition of BRM on Di19-PR module in response to drought.

Drought is one of the most important abiotic stresses, and seriously threatens plant development and productivity. Increasing evidence indicates that chromatin remodelers are pivotal for plant drought response. However, molecular mechanisms of chromatin remodelers-mediated plant drought responses remain obscure. In this study, we found a novel interactor of BRM called BRM-associated protein involved in drought response (BAPID), which interacted with SWI/SNF chromatin remodeler BRM and drought-induced transcription factor Di19. Our findings demonstrated that BAPID acted as a positive drought regulator since drought tolerance was increased in BAPID-overexpressing plants, but decreased in BAPID-deficient plants, and physically bound to PR1, PR2, and PR5 promoters to mediate expression of PR genes to defend against dehydration stress. Genetic approaches demonstrated that BRM acted epistatically to BAPID and Di19 in drought response in Arabidopsis. Furthermore, the BAPID protein-inhibited interaction between BRM and Di19, and suppressed the inhibition of BRM on the Di19-PR module by mediating the H3K27me3 deposition at PR loci, thus changing nucleosome accessibility of Di19 and activating transcription of PR genes in response to drought. Our results shed light on the molecular mechanism whereby the BAPID-BRM-Di19-PRs pathway mediates plant drought responses. We provide data improving our understanding of chromatin remodeler-mediated plant drought regulation network.

Historic dog Furs Unravel the Origin and Artificial Selection of Modern Nordic Lapphund and Elkhound dog Breeds.

The origins and extreme morphological evolution of the modern dog breeds are poorly studied because the founder populations are extinct. Here, we analyse eight 100 to 200 years old dog fur samples obtained from traditional North Swedish clothing, to explore the origin and artificial selection of the modern Nordic Lapphund and Elkhound dog breeds. Population genomic analysis confirmed the Lapphund and Elkhound breeds to originate from the local dog population, and showed a distinct decrease in genetic diversity in agreement with intense breeding. We identified eleven genes under positive selection during the breed development. In particular, the MSRB3 gene, associated with breed-related ear morphology, was selected in all Lapphund and Elkhound breeds, and functional assays showed that a SNP mutation in the 3'UTR region suppresses its expression through miRNA regulation. Our findings demonstrate analysis of near-modern dog artifacts as an effective tool for interpreting the origin and artificial selection of the modern dog breeds.

Leukotriene B4-induced neutrophil extracellular traps impede the clearance of Pneumocystis.

Pneumocystis pneumonia (PCP) is a fungal pulmonary disease with high mortality in immunocompromised patients. Neutrophils are essential in defending against fungal infections; however, their role in PCP is controversial. Here we aim to investigate the effects of neutrophil extracellular traps (NETs) on Pneumocystis clearance and lung injury using a mouse model of PCP. Intriguingly, although neutrophils play a fundamental role in defending against fungal infections, NETs failed to eliminate Pneumocystis, but instead impaired the killing of Pneumocystis. Mechanically, Pneumocystis triggered Leukotriene B4 (LTB4)-dependent neutrophil swarming, leading to agglutinative NET formation. Blocking Leukotriene B4 with its receptor antagonist Etalocib significantly reduced the accumulation and NET release of neutrophils in vitro and in vivo, enhanced the killing ability of neutrophils against Pneumocystis, and alleviated lung injury in PCP mice. This study identifies the deleterious role of agglutinative NETs in Pneumocystis infection and reveals a new way to prevent NET formation, which provides new insights into the pathogenesis of PCP.

N-acetyltransferase 10 regulates alphavirus replication via N4-acetylcytidine (ac4C) modification of the lymphocyte antigen six family member E (LY6E) mRNA.

Epitranscriptomic RNA modifications can regulate the stability of mRNA and affect cellular and viral RNA functions. The N4-acetylcytidine (ac4C) modification in the RNA viral genome was recently found to promote viral replication; however, the mechanism by which RNA acetylation in the host mRNA regulates viral replication remains unclear. To help elucidate this mechanism, the roles of N-acetyltransferase 10 (NAT10) and ac4C during the infection and replication processes of the alphavirus, Sindbis virus (SINV), were investigated. Cellular NAT10 was upregulated, and ac4C modifications were promoted after alphavirus infection, while the loss of NAT10 or inhibition of its N-acetyltransferase activity reduced alphavirus replication. The NAT10 enhanced alphavirus replication as it helped to maintain the stability of lymphocyte antigen six family member E mRNA, which is a multifunctional interferon-stimulated gene that promotes alphavirus replication. The ac4C modification was thus found to have a non-conventional role in the virus life cycle through regulating host mRNA stability instead of viral mRNA, and its inhibition could be a potential target in the development of new alphavirus antivirals.IMPORTANCEThe role of N4-acetylcytidine (ac4C) modification in host mRNA and virus replication is not yet fully understood. In this study, the role of ac4C in the regulation of Sindbis virus (SINV), a prototype alphavirus infection, was investigated. SINV infection results in increased levels of N-acetyltransferase 10 (NAT10) and increases the ac4C modification level of cellular RNA. The NAT10 was found to positively regulate SINV infection in an N-acetyltransferase activity-dependent manner. Mechanistically, the NAT10 modifies lymphocyte antigen six family member E (LY6E) mRNA-the ac4C modification site within the 3'-untranslated region (UTR) of LY6E mRNA, which is essential for its translation and stability. The findings of this study demonstrate that NAT10 regulated mRNA stability and translation efficiency not only through the 5'-UTR or coding sequence but also via the 3'-UTR region. The ac4C modification of host mRNA stability instead of viral mRNA impacting the viral life cycle was thus identified, indicating that the inhibition of ac4C could be a potential target when developing alphavirus antivirals.

Molecular mechanisms in MASLD/MASH-related HCC.

Liver cancer is the third leading cause of cancer-related deaths and ranks as the sixth most prevalent cancer type globally. NAFLD or metabolic dysfunction-associated steatotic liver disease, and its more severe manifestation, NASH or metabolic dysfunction-associated steatohepatitis (MASH), pose a significant global health concern, affecting approximately 20%-25% of the population. The increased prevalence of metabolic dysfunction-associated steatotic liver disease and MASH is parallel to the increasing rates of obesity-associated metabolic diseases, including type 2 diabetes, insulin resistance, and fatty liver diseases. MASH can progress to MASH-related HCC (MASH-HCC) in about 2% of cases each year, influenced by various factors such as genetic mutations, carcinogen exposure, immune microenvironment, and microbiome. MASH-HCC exhibits distinct molecular and immune characteristics compared to other causes of HCC and affects both men and women equally. The management of early to intermediate-stage MASH-HCC typically involves surgery and locoregional therapies, while advanced HCC is treated with systemic therapies, including anti-angiogenic therapies and immune checkpoint inhibitors. In this comprehensive review, we consolidate previous research findings while also providing the most current insights into the intricate molecular processes underlying MASH-HCC development. We delve into MASH-HCC-associated genetic variations and somatic mutations, disease progression and research models, multiomics analysis, immunological and microenvironmental impacts, and discuss targeted/combined therapies to overcome immune evasion and the biomarkers to recognize treatment responders. By furthering our comprehension of the molecular mechanisms underlying MASH-HCC, our goal is to catalyze the advancement of more potent treatment strategies, ultimately leading to enhanced patient outcomes.