Nobel Prize in Physiology or Medicine 2024 (2025)

Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA

• Amy E. Pasquinelli
• Brenda J. Reinhart
• Gary Ruvkun

The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans

• Brenda J. Reinhart
• Frank J. Slack
• Gary Ruvkun

Alternative temporal control systems for hypodermal cell differentiation in Caenorhabditis elegans

• Zhongchi Liu
• Victor Ambros

The Caenorhabditis elegans heterochronic gene lin-14 encodes a nuclear protein that forms a temporal developmental switch

• Gary Ruvkun
• John Giusto

A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans

• Jason Z. Morris
• Heidi A. Tissenbaum
• Gary Ruvkun

The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans

• Scott Ogg
• Suzanne Paradis
• Gary Ruvkun

Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant

• Ji Ying Sze
• Martin Victor
• Gary Ruvkun

Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes

• Kaveh Ashrafi
• Francesca Y. Chang
• Gary Ruvkun

A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity

• Siu Sylvia Lee
• Raymond Y.N. Lee
• Gary Ruvkun

Polygenic control of Caenorhabditis elegans fat storage

• Ho Yi Mak
• Laura S Nelson
• Gary Ruvkun

A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants

Although the soma ages during life, the germ line of multicellular organisms does not. Here it is shown that Caenorhabditis elegans mutants with increased longevity turn on gene expression programs in somatic tissue that are normally limited to the germ line; this may be the secret behind the increased health and lifespan of these mutant worms.

• Sean P. Curran
• Xiaoyun Wu
• Gary Ruvkun

MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability

During fasting, cellular lipophagy is activated and lipid stores are catabolized. O’Rourke and Ruvkun identify two metabolic transcriptional regulators, MXL-3 and HLH-30, which orchestrate the adaptive response to fasting by modulating the expression of lysosomal lipases and autophagy genes. In addition, they show that these regulators can influence C.elegans aging.

• Eyleen J. O’Rourke
• Gary Ruvkun

Lipid signalling couples translational surveillance to systemic detoxification in Caenorhabditis elegans

Through RNAi screens in C. elegans, Ruvkun and colleagues identify signalling pathways that induce detoxification genes following disrupted translation, suggesting translational surveillance of toxins and virulence factors.

• J. Amaranath Govindan
• Elamparithi Jayamani
• Gary Ruvkun

Caenorhabditis elegans has scores of homoeobox-containing genes

• Thomas R. Bürglin
• Michael Finney
• Gary Ruvkun

Systematic analysis of genes required for synapse structure and function

• Derek Sieburth
• QueeLim Ch'ng
• Joshua M. Kaplan

Somatic misexpression of germline P granules and enhanced RNA interference in retinoblastoma pathway mutants

• Duo Wang
• Scott Kennedy
• Gary Ruvkun

Potent effect of target structure on microRNA function

• Dang Long
• Rosalind Lee
• Ye Ding

The exonuclease ERI-1 has a conserved dual role in 5.8S rRNA processing and RNAi

• Harrison W Gabel
• Gary Ruvkun

Trans-splicing in C. elegans generates the negative RNAi regulator ERI-6/7

• Sylvia E. J. Fischer
• Maurice D. Butler
• Gary Ruvkun

Caenorhabditis elegans pathways that surveil and defend mitochondria

A genome-wide RNA interference screen in Caenorhabditis elegans identifies 45 genes with roles in protective pathways following drug- and genetic-disruption-induced mitochondrial inhibition.

• Ying Liu
• Buck S. Samuel
• Gary Ruvkun

Identification of small RNA pathway genes using patterns of phylogenetic conservation and divergence

To identify comprehensively factors involved in RNAi and microRNA-mediated gene expression regulation, this study performed a phylogenetic analysis of 86 eukaryotic species; the candidates this approach highlighted were subjected to Bayesian analysis with transcriptional and proteomic interaction data, identifying protein orthologues of already known RNAi silencing factors, as well as other hits involved in splicing, suggesting a connection between the two processes.

• Yuval Tabach
• Allison C. Billi
• Gary Ruvkun

Biodistribution and function of extracellular miRNA-155 in mice

• Shashi Bala
• Timea Csak
• Gyongyi Szabo

DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity

FOXO transcription factors confer stress resistance and longevity in several organisms. Ruvkun and colleagues demonstrate in Caenorhabditis elegans that DAF-16 (FOXO homologue) recruits the chromatin remodeller SWI/SNF to target genes. They show that SWI/SNF is required for DAF-16-mediated functions such as dauer formation, stress resistance and increasing longevity.

• Christian G. Riedel
• Robert H. Dowen
• Gary Ruvkun

DAF-16/FOXO and HLH-30/TFEB function as combinatorial transcription factors to promote stress resistance and longevity

The transcription factor DAF-16/FOXO is a downstream effector of insulin/insulin-like growth factor signaling and plays an important role in stress resistance and longevity. Here, the authors show that DAF-16/FOXO can form a complex with HLH-30/TFEB to synergistically regulate transcription of target genes in response to certain stress stimuli.

• Xin-Xuan Lin
• Ilke Sen
• Christian G. Riedel

A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans

• Scott Kennedy
• Duo Wang
• Gary Ruvkun

The functions of animal microRNAs

• Victor Ambros

Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs

• David P. Bartel
• Chang-Zheng Chen

RNA and microRNAs in fragile X mental retardation

• Peng Jin
• Reid S. Alisch
• Stephen T. Warren

Canalization of development by microRNAs

• Eran Hornstein
• Noam Shomron

Functions of microRNAs and related small RNAs in plants

• Allison C Mallory
• Hervé Vaucheret

Small silencing RNAs: an expanding universe

Small RNAs — including miRNAs, siRNAs and piRNAs — differ in their biogenesis, modes of target regulation and biological functions. There are also interconnections between these pathways, which compete and collaborate in some of their regulatory and protective roles.

• Megha Ghildiyal
• Phillip D. Zamore

Many roads to maturity: microRNA biogenesis pathways and their regulation

• Julia Winter
• Stephanie Jung
• Sven Diederichs

Evolution of microRNA diversity and regulation in animals

Our increasing understanding of microRNA biology, combined with sequence information from diverse animal genomes, has shed light on how microRNAs and their targets evolve and how the evolution of microRNA-containing regulatory networks has contributed to organismal complexity.

• Eugene Berezikov

MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship

MicroRNAs are key regulators of gene expression. Emerging evidence points towards a reciprocal relationship between microRNAs and their targets and for roles of non-target RNAs and proteins in this crosstalk.

• Amy E. Pasquinelli

DICER1: mutations, microRNAs and mechanisms

Germline mutations inDICER1 can lead to DICER1 syndrome, which is characterized by the predisposition of various types of cancer in childhood and during early adulthood. Additionally, specific DICER1 mutations occur in tumours. This Review discusses germline and somatically-acquired DICER1mutations and their effects on tumorigenesis.

• William D. Foulkes
• John R. Priest
• Thomas F. Duchaine

MicroRNA biogenesis pathways in cancer

The microRNA (miRNA) biogenesis pathway is frequently altered in cancer, leading to global downregulation of miRNA levels in some cancer types. This Review discusses the alterations that affect miRNA biogenesis in cancer.

• Shuibin Lin
• Richard I. Gregory

Towards a molecular understanding of microRNA-mediated gene silencing

MicroRNAs (miRNAs) repress gene expression both through initiating mRNA degradation and through translational repression. This Review describes how molecular studies and structural data are revealing key insights into both mechanisms of miRNA-mediated gene repression in animals, including their intricate interplay, and are posing new questions for future research.

• Stefanie Jonas
• Elisa Izaurralde

The evolutionary origin of plant and animal microRNAs

miRNAs are crucial regulators of normal development in plants and animals, but their origins remain obscure. Exploration of the similarities and differences between different miRNA pathways help to elucidate their origins and role.

• Yehu Moran
• Maayan Agron
• Ulrich Technau

Regulation of microRNA function inanimals

MicroRNAs (miRNAs) are key regulators of biological processes. Recent discoveries have expanded our understanding of the control of miRNA function in animals, through alternative processing, miRNA-sequence editing, post-translational modifications of Argonaute proteins, subcellular localization and regulation of miRNA–target interactions.

• Luca F. R. Gebert
• Ian J. MacRae

Control of metastatic progression by microRNA regulatory networks

Pencheva and Tavazoie discuss the recent advances in understanding how microRNAs control metastatic progression in cancer.

• Nora Pencheva
• Sohail F. Tavazoie

Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications

A growing body of evidence implicates non-coding RNAs (ncRNAs) in liver carcinogenesis. In this Review, the authors summarize the pathological roles of ncRNAs in hepatocellular carcinoma and explore the potential applications of ncRNAs as diagnostic tools and therapeutic targets.

• Chun-Ming Wong
• Felice Ho-Ching Tsang
• Irene Oi-Lin Ng

Tapping the RNA world for therapeutics

Developments in basic RNA biology have spawned RNA-based strategies to generate new types of therapeutics. Judy Lieberman reviews RNA-based drug design and discusses barriers to more widespread applications and possible ways to overcome them.

• Judy Lieberman

Regulation of microRNA biogenesis and its crosstalk with other cellular pathways

The cleavage of microRNA (miRNA) precursors by Drosha and Dicer and their loading with Argonaute proteins into RNA-induced silencing complexes are key steps in miRNA biogenesis. Recent studies have clarified the mechanisms of action of these molecular machines and discovered non-canonical miRNA biogenesis pathways.

• Thomas Treiber
• Nora Treiber
• Gunter Meister

The clinical potential of circulating microRNAs in obesity

Circulating microRNAs act as a new class of endocrine factor that can facilitate crosstalk between metabolic organs. This Review highlights obesity-associated and/or adipose tissue-enriched microRNAs and discusses their potential as biomarkers or therapeutics for obesity and related disorders.

• Chenbo Ji
• Xirong Guo

MicroRNAs as regulators of brain function and targets for treatment of epilepsy

In this Review, Brennan and Henshall discuss how microRNAs determine and control neuronal and glial functions, how this process is altered in states associated with hyperexcitability, and the prospects for microRNA targeting for the treatment of epilepsy.

• Gary P. Brennan
• David C. Henshall

MicroRNA-mediated regulation of glucose and lipid metabolism

MicroRNAs widely regulate systemic metabolism, prominently that of glucose and lipids. Consequently, microRNA misexpression can lead to metabolic diseases such as diabetes and atherosclerosis. MicroRNAs are therefore emerging as potential therapeutic targets to control metabolism and, owing to their secretion in extracellular vesicles, as metabolic biomarkers.

• Pamela Agbu
• Richard W. Carthew

Exploring the expanding universe of small RNAs

Shi et al. discuss recent approaches for the discovery of small noncoding RNAs (sncRNAs), limitations associated with sncRNA expression analyses, and emerging methods for direct and simultaneous detection of multiple RNA modifications.

• Junchao Shi
• Tong Zhou
• Qi Chen

microRNAs in action: biogenesis, function and regulation

In this Review, the authors describe how the application of new technologies to the microRNA (miRNA) field has yielded key insights into miRNA biology. The authors summarize our current understanding of miRNA biogenesis, function and processing, and highlight challenges to address in future research.

• Renfu Shang
• Seungjae Lee
• Eric C. Lai

Circulating non-coding RNA biomarkers of endocrine tumours

Circulating non-coding RNA (ncRNA) molecules are being investigated as biomarkers of endocrine tumours of the pituitary, parathyroid, pancreas and adrenal glands. This Review outlines ncRNA biology, before discussing research findings on ncRNAs in endocrine tumours and their potential utility as biomarkers, ending with an outlook for future studies.

• Henriett Butz
• Attila Patócs
• Peter Igaz

Non-coding RNAs in disease: from mechanisms to therapeutics

In this Review, the authors describe our current knowledge of the role of microRNAs, long non-coding RNAs and circular RNAs in disease, with a focus on cardiovascular, neurological, infectious diseases and cancer. Further, they discuss the potential use of non-coding RNAs as disease biomarkers and as therapeutic targets.

• Kinga Nemeth
• Recep Bayraktar
• George A. Calin

Role for a bidentate ribonuclease in the initiation step of RNA interference

• Emily Bernstein
• Amy A. Caudy
• Gregory J. Hannon

Dicer is essential for mouse development

• Emily Bernstein
• Sang Yong Kim
• Gregory J Hannon

The microRNA-producing enzyme Dicer1 is essential for zebrafish development

• Erno Wienholds
• Marco J Koudijs
• Ronald H A Plasterk

Ancient animal microRNAs and the evolution of tissue identity

Recent work suggests that microRNAs might have been important in the evolution of complexity in multicellular animals. Here it is shown that the most ancient known microRNA, miR–100, was initially active in neurosecretory cells around the mouth. Other highly conserved varieties were first present in specific tissues and organ systems. Thus, microRNA expression was initially restricted to an ancient set of ancient animal cell types and tissues.

• Foteini Christodoulou
• Florian Raible
• Detlev Arendt

Early origins and evolution of microRNAs and Piwi-interacting RNAs in animals

• Andrew Grimson
• Mansi Srivastava
• David P. Bartel

The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans

• Nicole King
• M. Jody Westbrook
• Daniel Rokhsar

Functional screenings reveal different requirements for host microRNAs in Salmonella and Shigella infection

This study reports a microscopy-based screen to find microRNAs (miRNAs) that control infection by Salmonella and Shigella, showing they have different requirements. Two miRNAs decrease Shigella actin motility through N-WASP and one miRNA inhibits Salmonella by targeting TGS2, a regulator of phagolysosomal trafficking.

• Carmen Aguilar
• Ana Rita Cruz
• Ana Eulalio

Melanoma miRNA trafficking controls tumour primary niche formation

Dror etal.report that melanoma-derived melanosomes carry miRNAs that induce primary fibroblast reprogramming into cancer-associated fibroblasts, and also induce the formation of a pro-tumorigenic niche.

• Shani Dror
• Laureen Sander
• Carmit Levy

MicroRNAs can generate thresholds in target gene expression

Alexander van Oudenaarden and colleagues examine microRNA-mediated regulation of gene expression using single-cell measurements of a target gene's expression. They find that microRNAs can repress gene expression either as a switch or through fine-tuning and that the strength of repression can vary widely between cells.

• Shankar Mukherji
• Margaret S Ebert
• Alexander van Oudenaarden

Cell-type-specific profiling of loaded miRNAs from Caenorhabditis elegans reveals spatial and temporal flexibility in Argonaute loading

C. elegans miRNAs associate with AGO proteins ALG-1 and ALG-2. Here the authors provide a map of miRNAs loaded into ALG-1 and ALG-2 from intestine, body wall muscles and nervous system in C. elegans providing insights into spatial and temporal AGO loading flexibility.

• Christopher A. Brosnan
• Alexander J. Palmer
• Steven Zuryn

Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans

• Andrew Fire
• SiQun Xu
• Craig C. Mello

A genetic pathway for the specification of the vulval cell lineages of Caenorhabditis elegans

• Edwin L. Ferguson
• Paul W. Sternberg
• H. Robert Horvitz

Impaired microRNA processing enhances cellular transformation and tumorigenesis

• Madhu S Kumar
• Jun Lu
• Tyler Jacks

Widespread microRNA repression by Myc contributes to tumorigenesis

• Tsung-Cheng Chang
• Duonan Yu
• Joshua T Mendell

Pseudouridine guides germline small RNA transport and epigenetic inheritance

Germline small RNAs in plants and mammals are marked by pseudouridine. In plants, Exportin-t is required for pseudouridylation, transport and localization of small RNAs in pollen, as well as for epigenetic inheritance in the form the triploid block.

• Rowan P. Herridge
• Jakub Dolata
• Robert A. Martienssen

A microRNA-inducible CRISPR–Cas9 platform serves as a microRNA sensor and cell-type-specific genome regulation tool

Wang et al. developed an inducible CRISPR–Cas9 system, in which guide RNA release is controlled by specific microRNAs, and demonstrated its application as a microRNA sensor and cell-type-specific genome regulator.

• Xi-Wen Wang
• Lu-Feng Hu
• Yangming Wang

miRNAs confer phenotypic robustness to gene networks by suppressing biological noise

MicroRNAs are thought to confer robustness to biological processes, but clear experimental evidence is still needed. Here, Siciliano et al. construct a toggle-switch in mammalian cells to show that microRNAs buffer fluctuations in protein levels, thereby providing phenotypic robustness to gene regulatory networks.

• Velia Siciliano
• Immacolata Garzilli
• Diego di Bernardo

p53 regulates epithelial–mesenchymal transition and stem cell properties through modulating miRNAs

The epithelial to mesenchymal transition (EMT) has been recently associated with a stem cell phenotype. In breast cancer cell lines and tumours, p53 directly targets the expression of microRNAs that have been shown to inhibit EMT and stem cells regulators.

• Chun-Ju Chang
• Chi-Hong Chao
• Mien-Chie Hung

Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells

Cellular senescence is partly caused by RB1/E2F-mediated repression of proliferation genes. Bischof and colleagues now demonstrate that RB1 interacts with the microRNA effector AGO2, and that AGO2 and the microRNA let-7 are needed for chromatin remodelling and repression of E2F-target loci.

• Moussa Benhamed
• Utz Herbig
• Oliver Bischof

RNA helicase Brr2a promotes miRNA biogenesis by properly remodelling secondary structure of pri-miRNAs

RNA secondary structure is a new regulatory layer of transcript fates. Here, Li et al. find that plant RNA helicase Brr2a, acting beyond its canonical role in spliceosome, can optimize secondary structure of pri-miRNAs to promote miRNA production.

• Xindi Li
• Songxiao Zhong
• Xiuren Zhang

MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells

• Margaret S Ebert
• Joel R Neilson
• Phillip A Sharp

Linking key steps of microRNA biogenesis by TREX-2 and the nuclear pore complex in Arabidopsis

This study shows that the Arabidopsis TREX-2 complex coordinates the transcription, processing and export steps in miRNA biogenesis, and that it acts with the nucleoporin NUP1 in miRNA export.

• Bailong Zhang
• Chenjiang You
• Xuemei Chen

Gain-of-function mutation of microRNA-140 in human skeletal dysplasia

Clinical insights from patients with a rare genetic skeletal disorder led to the discovery of the first case of a pathogenic gain-of-function miRNA mutation.

• Giedre Grigelioniene
• Hiroshi I. Suzuki
• Tatsuya Kobayashi

Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss

Miguel Moreno-Pelayo and colleagues report mutations in the seed region of human miR-96 segregating with progressive hearing loss in two families. In an accompanying paper, Karen Steel and colleagues show that the mouse diminuendo mutant, which also shows progressive hearing loss, carries a similar mutation in the seed region of mouse miR-96.

• Ángeles Mencía
• Silvia Modamio-Høybjør
• Miguel Ángel Moreno-Pelayo

The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition

Human Long INterspersed Element class 1 (LINE-1) elements are expressed and mobilized in many types of cancer, contributing to malignancy. Here the authors show that the tumorsuppressor microRNA let-7 targets the LINE-1 mRNA and reduces LINE-1 mobilization.

• Pablo Tristán-Ramos
• Alejandro Rubio-Roldan
• Sara R. Heras

Medicine Nobel awarded for gene-regulating ‘microRNAs’

Victor Ambros and Gary Ruvkun identified a class of tiny molecules that have a crucial role in controlling gene expression.

• Ewen Callaway
• Katharine Sanderson

Don't hold your breath

In some organisms a reduced-calorie diet increases lifespan. Conventional thinking about the mechanism involved now comes under question from the results of experiments with yeast.

• Siu Sylvia Lee
• Gary Ruvkun

The evolution of our thinking about microRNAs

• Victor Ambros

A molecular growth industry

• Gary Ruvkun

One small step for worms, one giant leap for small RNAs

Two studies in nematodes revolutionized our understanding of gene regulation by identifying and functionally characterizing the first microRNA, lin-4.

• Phillip D. Zamore

CLIP and complementary methods

Ule and colleagues discuss cross-linking and immunoprecipitation (CLIP) methods for characterizing the RNA binding partners of RNA-binding proteins and explore the data analysis workflows, best practices and applications for these techniques. The Primer also considers methods for characterizing the protein binding partners of specific RNAs and discusses how data from these complementary methods can be integrated into CLIP workflows.

• Markus Hafner
• Maria Katsantoni
• Mihaela Zavolan

Putting together pieces of the LIN28A pathway puzzle

Two recent studies provide mechanistic insights into how LIN28A controls changes in cell fate identity, focusing on either a let-7-independent or let-7-dependent pathway of action involving LIN28A.

• Alperen Yilmaz
• Gulben Gurhan
• Jacob H. Hanna