An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Chaperone-mediated autophagy (CMA), a lysosome-dependent protein degradation pathway, plays a pivotal yet poorly understood role in cellular senescence-related degenerative diseases. Our study sheds light on a novel mechanism whereby UCHL1 plays a crucial role in mitigating nucleus pulposus cell (NPC) senescence and intervertebral disc degeneration (IVDD) by activating CMA to counteract autophagy-dependent ferroptosis. Through sequencing analysis of human samples, we identified UCHL1 as a potential factor influencing disc degeneration. Further research revealed that UCHL1 activates CMA by stabilizing HSPA8 through deubiquitination. HSPA8, in turn, recognizes and promotes the degradation of HPCAL1 via the CMA pathway by binding to its “KFERQ” motif, ultimately alleviating NPC senescence. Importantly, we demonstrated that engineered exosomes delivering UCHL1-overexpressing plasmids effectively alleviated NPC senescence and significantly mitigated the progression of IVDD. This finding underscores the significance of CMA-regulated ferroptosis in IVDD through UCHL1 modulation and as a promising target for improving chronic pain and IVDD progression. Abbreviations: AAV: adeno-associated virus; AB: Alcian Blue; ACSL4: acyl-CoA synthetase long chain family member 4; ALP: autophagy-lysosome pathway; Baf-A1: bafilomycin A1; CHX: cycloheximide; CMA: chaperone-mediated autophagy; Co-IP: co-immunoprecipitation; DUBs: deubiquitinating enzymes; eMI: endosomal microautophagy; Evs: extracellular vesicles; Exo: exosome; GPX4: glutathione peroxidase 4; H&E: hematoxylin and eosin; HsNPCs: Human NPCs; IF: immunofluorescence; IHC: immunohistochemistry; IP-MS: immunoprecipitation mass spectrometry; IVDD: intervertebral disc degeneration; IVDs: intervertebral discs; LBP: low back pain; LDP: lumbar disc prolapse; MRI: magnetic resonance imaging; N/L: NH4Cl and leupeptin; NP: nucleus pulposus; NPCs: nucleus pulposus cells; PCA: principal component analysis; qRT-PCR: quantitative real-time PCR; RnBMSCs: rat bone marrow mesenchymal stem cells; RnNPCs: rat NPCs; ROS: reactive oxygen species; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; SD: Sprague-Dawley; SO: Safranin O-Fast Green; TBHP: tert-butyl hydroperoxide; UCHL1: ubiquitin C-terminal hydrolase L1; UPS: ubiquitin-proteasome system

Chaperone-mediated autophagy (CMA), a lysosome-dependent protein degradation pathway, plays a pivotal yet poorly understood role in cellular senescence-related degenerative diseases. Our study sheds light on a novel mechanism whereby UCHL1 plays a crucial role in mitigating nucleus pulposus cell (NPC) senescence and intervertebral disc degeneration (IVDD) by activating CMA to counteract autophagy-dependent ferroptosis. Through sequencing analysis of human samples, we identified UCHL1 as a potential factor influencing disc degeneration. Further research revealed that UCHL1 activates CMA by stabilizing HSPA8 through deubiquitination. HSPA8, in turn, recognizes and promotes the degradation of HPCAL1 via the CMA pathway by binding to its “KFERQ” motif, ultimately alleviating NPC senescence. Importantly, we demonstrated that engineered exosomes delivering UCHL1-overexpressing plasmids effectively alleviated NPC senescence and significantly mitigated the progression of IVDD. This finding underscores the significance of CMA-regulated ferroptosis in IVDD through UCHL1 modulation and as a promising target for improving chronic pain and IVDD progression. Abbreviations: AAV: adeno-associated virus; AB: Alcian Blue; ACSL4: acyl-CoA synthetase long chain family member 4; ALP: autophagy-lysosome pathway; Baf-A1: bafilomycin A1; CHX: cycloheximide; CMA: chaperone-mediated autophagy; Co-IP: co-immunoprecipitation; DUBs: deubiquitinating enzymes; eMI: endosomal microautophagy; Evs: extracellular vesicles; Exo: exosome; GPX4: glutathione peroxidase 4; H&E: hematoxylin and eosin; HsNPCs: Human NPCs; IF: immunofluorescence; IHC: immunohistochemistry; IP-MS: immunoprecipitation mass spectrometry; IVDD: intervertebral disc degeneration; IVDs: intervertebral discs; LBP: low back pain; LDP: lumbar disc prolapse; MRI: magnetic resonance imaging; N/L: NH4Cl and leupeptin; NP: nucleus pulposus; NPCs: nucleus pulposus cells; PCA: principal component analysis; qRT-PCR: quantitative real-time PCR; RnBMSCs: rat bone marrow mesenchymal stem cells; RnNPCs: rat NPCs; ROS: reactive oxygen species; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; SD: Sprague-Dawley; SO: Safranin O-Fast Green; TBHP: tert-butyl hydroperoxide; UCHL1: ubiquitin C-terminal hydrolase L1; UPS: ubiquitin-proteasome system

Tectonic configuration of the Rodinia Supercontinent and palaeogeographic framework of terranes incorporated into the Tibetan Plateau remain enigmatic due to the paucity of Neoproterozoic crystalline outcrops. The Amdo Terrane, emplaced in the central Tibetan Plateau, plays a key role in regulating the Precambrian geodynamics of the Himalayan–Tibetan Orogen. Recent investigations regarding Amdo Neoproterozoic orthogneisses have elucidated their petrogenesis and tectonic implications; however, their wide range of crystallization ages (ca. 910–767 Ma) and differentiated geochemical characters (e.g. varied SiO₂ contents of 45.83–78.92 wt. %, etc.) leave the Precambrian origin and tectono-thermal evolution of the Amdo Terrane controversial. In this contribution, we present comprehensive geochemical and geochronological datasets concerning reported Amdo Neoproterozoic orthogneisses, accompanied by comparative analyses and interpretive discussions. These Amdo orthogneisses are predominantly granitic gneisses; the majority of these granitoids (Gg-1, ca. 893–767 Ma) exhibit high-K calc–alkaline compositions and heterogenous zircon εHf_(t) values (−9.3 to + 7.0), indicating derivation from multiple magma sources. Their negative Nb, Ta, and Ti anomalies, coupled with volcanic-arc (VAG) or syn-collision granites (syn-COLG) affinities suggest Gg-1 belong to an Andean-type arc setting. The other group of granitic gneisses (Gg-2, ca. 820, 802, and 801 Ma) display geochemical signatures typical of A2-type granites, with elevated concentrations of high-field strength elements (HFSEs, Zr+Nb+Ce+Y > 330 ppm) and high Y/Nb, Rb/Nb, Ce/Nb, Sc/Nb, and Yb/Ta ratios. Integrated with the coeval Amdo arc-related granitoids and back-arc igneous rocks (initiated at ca. 839 Ma) in the Present-day North Lhasa Terrane (PNL), we perceive that Amdo Gg-2 gneisses may represent products of a back-arc extensional environment driven by upward counterflow of asthenosphere. Moreover, subordinate intermediate orthogneisses may be granitic variants after moderate mantle contributions; likewise, they could also be classified into arc (Gi-1, ca. 807 and 767 Ma) and back-arc (Gi-2, ca. 842 and 824 Ma) groups based on their distinct geochemical features and tectonic conditions. Additionally, the rarely reported basaltic gneisses (gneissic amphibolites, ca. 863 Ma) are overprint by E-MORB traits (relatively high Nb/Yb, Zr/Y ratios and slightly right-inclined rare earth element patterns), possibly defining evolved remnants of the reduced Mozambique oceanic crust. We tentatively interpret the Amdo Terrane as the western segment of Original North Lhasa Block (ONL, comprising the PNL and Amdo Terrane). After rift-related magmatism (separation from the Rodinia) triggered by a mantle plume (ca. 925–900 Ma), the ONL initiated westward drifting and underwent protracted oceanic subduction by Mozambique; thus, generating extensive volcanic-arc granitoids in the western domain of ONL, especially of the Amdo part (ca. 893–857 Ma). Subsequent rollback of the deeply subducted oceanic slab (possibly started at ca. 850 Ma) induced asthenospheric upwelling and back-arc extension, giving birth to the high-temperature A2-type granitoids (ca. 842–801 Ma). Furthermore, the westward transporting history of Amdo Terrane could be further extended considering the younger Andean-type magmatic events (ca. 838–767 Ma). In addition, the E-MORB-like amphibolite gneisses (ca. 863 Ma) entrained within the Amdo Terrane might fingerprint allochthonous intra-oceanic fragments after within-plate enrichment which were scraped onto the western active continental margin of ONL due to the subduction of the Mozambique Ocean.

Tectonic configuration of the Rodinia Supercontinent and palaeogeographic framework of terranes incorporated into the Tibetan Plateau remain enigmatic due to the paucity of Neoproterozoic crystalline outcrops. The Amdo Terrane, emplaced in the central Tibetan Plateau, plays a key role in regulating the Precambrian geodynamics of the Himalayan–Tibetan Orogen. Recent investigations regarding Amdo Neoproterozoic orthogneisses have elucidated their petrogenesis and tectonic implications; however, their wide range of crystallization ages (ca. 910–767 Ma) and differentiated geochemical characters (e.g. varied SiO₂ contents of 45.83–78.92 wt. %, etc.) leave the Precambrian origin and tectono-thermal evolution of the Amdo Terrane controversial. In this contribution, we present comprehensive geochemical and geochronological datasets concerning reported Amdo Neoproterozoic orthogneisses, accompanied by comparative analyses and interpretive discussions. These Amdo orthogneisses are predominantly granitic gneisses; the majority of these granitoids (Gg-1, ca. 893–767 Ma) exhibit high-K calc–alkaline compositions and heterogenous zircon εHf_(t) values (−9.3 to + 7.0), indicating derivation from multiple magma sources. Their negative Nb, Ta, and Ti anomalies, coupled with volcanic-arc (VAG) or syn-collision granites (syn-COLG) affinities suggest Gg-1 belong to an Andean-type arc setting. The other group of granitic gneisses (Gg-2, ca. 820, 802, and 801 Ma) display geochemical signatures typical of A2-type granites, with elevated concentrations of high-field strength elements (HFSEs, Zr+Nb+Ce+Y > 330 ppm) and high Y/Nb, Rb/Nb, Ce/Nb, Sc/Nb, and Yb/Ta ratios. Integrated with the coeval Amdo arc-related granitoids and back-arc igneous rocks (initiated at ca. 839 Ma) in the Present-day North Lhasa Terrane (PNL), we perceive that Amdo Gg-2 gneisses may represent products of a back-arc extensional environment driven by upward counterflow of asthenosphere. Moreover, subordinate intermediate orthogneisses may be granitic variants after moderate mantle contributions; likewise, they could also be classified into arc (Gi-1, ca. 807 and 767 Ma) and back-arc (Gi-2, ca. 842 and 824 Ma) groups based on their distinct geochemical features and tectonic conditions. Additionally, the rarely reported basaltic gneisses (gneissic amphibolites, ca. 863 Ma) are overprint by E-MORB traits (relatively high Nb/Yb, Zr/Y ratios and slightly right-inclined rare earth element patterns), possibly defining evolved remnants of the reduced Mozambique oceanic crust. We tentatively interpret the Amdo Terrane as the western segment of Original North Lhasa Block (ONL, comprising the PNL and Amdo Terrane). After rift-related magmatism (separation from the Rodinia) triggered by a mantle plume (ca. 925–900 Ma), the ONL initiated westward drifting and underwent protracted oceanic subduction by Mozambique; thus, generating extensive volcanic-arc granitoids in the western domain of ONL, especially of the Amdo part (ca. 893–857 Ma). Subsequent rollback of the deeply subducted oceanic slab (possibly started at ca. 850 Ma) induced asthenospheric upwelling and back-arc extension, giving birth to the high-temperature A2-type granitoids (ca. 842–801 Ma). Furthermore, the westward transporting history of Amdo Terrane could be further extended considering the younger Andean-type magmatic events (ca. 838–767 Ma). In addition, the E-MORB-like amphibolite gneisses (ca. 863 Ma) entrained within the Amdo Terrane might fingerprint allochthonous intra-oceanic fragments after within-plate enrichment which were scraped onto the western active continental margin of ONL due to the subduction of the Mozambique Ocean.

Multi-component crustal sources are universally acknowledged as the overriding factor in causing geochemical heterogeneities of the Cenozoic Himalayan leucogranites. In previous studies, metasedimentary rocks from the Greater Himalayan Crystalline Complex were always underlined to be the dominant origin for leucogranites after the Eocene and Oligocene transition (ca. <36 Ma). However, given that the petrological diversity of the Greater Himalayas, especially the widespread and high-grade metamorphosed granitic gneisses; this traditional standpoint has been increasingly questioned nowadays. To further demonstrate the role of granitic gneiss in leucogranite generation, a rounded compilation of geochronological and geochemical data for leucogranites, granitic gneisses, and other related rocks from the specified N – S striking Yardoi – Cuonadong – Tsona transect has been conducted. After making comprehensive comparison and discussion between leucogranites and granitic gneisses, we argue that Cenozoic Himalayan leucogranites may not be pure metasediments derived S-type granites as orthogneisses could be another important endmember for the provenance of them based on the following evidence: (1) Abundant relict zircons within the Himalayan leucogranites display two evident U – Pb age clusters at ca. 850–800 Ma and ca. 520–470 Ma, which are contemporaneous with the Neoproterozoic and early Paleozoic granitic magmatism, respectively. (2) Zircon Hf isotopes of Himalayan-aged rims (−11.21 to −4.82) could be perfectly constrained by two evolution lines derived from Neoproterozoic (−6.40 to 0.16) and early Paleozoic (−2.37 to 6.15) zircon groups. (3) In terms of whole-rock Sr – Nd isotopes (all corrected to 20 Ma), there is a notable overlap between leucogranites (0.7142 to 0.8429 for Sr; and −17.34 to −9.86 for Nd) and granitic gneisses (0.7703 to 0.8716 for Sr, and −16.27 to −9.80 for Nd). (4) Although the fertility of granitic gneisses should be poorest in the absence of a separate aqueous phase; however, the evolutionary P – T – XH₂O conditions triggered by compressional thrust activity of the Main Central Thrust and arc-parallel extension have remarkably modified original source structures (infiltration by LHS-derived fluids) and melting behaviours (more recognized fluid-present partial melting cases). Consequently, the role the granitic gneisses would be strengthened because of the greatly improved fertility via fluid-present melting; and the Sr – Nd isotopic signatures of Himalayan leucogranites would be spatially-temporally evolved.

Multi-component crustal sources are universally acknowledged as the overriding factor in causing geochemical heterogeneities of the Cenozoic Himalayan leucogranites. In previous studies, metasedimentary rocks from the Greater Himalayan Crystalline Complex were always underlined to be the dominant origin for leucogranites after the Eocene and Oligocene transition (ca. <36 Ma). However, given that the petrological diversity of the Greater Himalayas, especially the widespread and high-grade metamorphosed granitic gneisses; this traditional standpoint has been increasingly questioned nowadays. To further demonstrate the role of granitic gneiss in leucogranite generation, a rounded compilation of geochronological and geochemical data for leucogranites, granitic gneisses, and other related rocks from the specified N – S striking Yardoi – Cuonadong – Tsona transect has been conducted. After making comprehensive comparison and discussion between leucogranites and granitic gneisses, we argue that Cenozoic Himalayan leucogranites may not be pure metasediments derived S-type granites as orthogneisses could be another important endmember for the provenance of them based on the following evidence: (1) Abundant relict zircons within the Himalayan leucogranites display two evident U – Pb age clusters at ca. 850–800 Ma and ca. 520–470 Ma, which are contemporaneous with the Neoproterozoic and early Paleozoic granitic magmatism, respectively. (2) Zircon Hf isotopes of Himalayan-aged rims (−11.21 to −4.82) could be perfectly constrained by two evolution lines derived from Neoproterozoic (−6.40 to 0.16) and early Paleozoic (−2.37 to 6.15) zircon groups. (3) In terms of whole-rock Sr – Nd isotopes (all corrected to 20 Ma), there is a notable overlap between leucogranites (0.7142 to 0.8429 for Sr; and −17.34 to −9.86 for Nd) and granitic gneisses (0.7703 to 0.8716 for Sr, and −16.27 to −9.80 for Nd). (4) Although the fertility of granitic gneisses should be poorest in the absence of a separate aqueous phase; however, the evolutionary P – T – XH₂O conditions triggered by compressional thrust activity of the Main Central Thrust and arc-parallel extension have remarkably modified original source structures (infiltration by LHS-derived fluids) and melting behaviours (more recognized fluid-present partial melting cases). Consequently, the role the granitic gneisses would be strengthened because of the greatly improved fertility via fluid-present melting; and the Sr – Nd isotopic signatures of Himalayan leucogranites would be spatially-temporally evolved.

The widespread Cenozoic Himalayan leucogranites (HLs) are representative rocks evolving from relatively pure crust-derived melts with few mantle material inputs and are believed to be highly fractionated and rare-metal mineralization developed. Over the past several decades, high-quality geochronological and geochemical analyses for the HLs have facilitated exploring the metamorphism, deformation, anatexis, and tectonic settings, enabling us to decipher the evolution process of the Himalayan orogen. In this study, we collected a large amount of geochronological, geochemical, and thermodynamic data from previous studies. Generally, the HLs exhibit (strongly) peraluminous (1.06–1.22) features and are characterized by high SiO₂ (70.95–75.08 wt. %) and Al₂O₃ (14.18–15.85 wt. %) and low TiO₂ (0.02–0.26 wt. %), MgO (0.07–0.73 wt. %), MnO (0.01–0.07 wt. %), and total iron (FeO_T = 0.44–1.71 wt. %) contents, and are enriched in large ion lithophile elements (e.g. K, Rb, Pb, U). Moreover, rare-metal elements (Li, Be, Ta, W, Sn) also show their enrichments in the HLs; and the deviations of K/Rb (72.16–190.45), Zr/Hf (15.00–35.19), Nb/Ta (2.65–12.75), and Y/Ho (26.07–36.75) ratios from the chondritic values are also notable. All these geochemical structures above suggest that the HLs are (highly) fractionated. Considering the diverging whole-rock isotopic Sr and Nd compositions of the HLs, with the (⁸⁷Sr/⁸⁶Sr)_t ratios and εNd_(t) values mostly ranging from 0.7159 to 0.8052 and −16.78 to −10.43, respectively, the source rocks of the HLs should be multiplex. Additionally, different melting mechanisms (including fluid-absent/present partial melting of muscovite, biotite, and hornblende) can be identified in the HL productions. The occurrences of beryl (Be), columbite (Nb and Ta), spodumene (Li), and many other rare-metal minerals have been frequently reported recently, suggesting the enrichment of rare-metal elements associated with the HLs. To provide a comprehensive and meticulous summary of these HLs (1593 leucogranite samples), we divide them into five stages based on different tectonic backgrounds. After comparing them, we propose that: (1) from Stage I to V, the HL emplacements were strongly related to the tectonic backgrounds: thickened crust from ca. 49 to 40 Ma (I), transition from compression to N-S extension (onset of the South Tibetan Detachment System (STDS)) from ca. 39 to 30 Ma (II), large-scale N-S extension (active movement of the STDS) from ca. 29 to 15 Ma (III), N-S extension to E-W extension tectonic transition (construction of N-S trending rifts (NSTRs)) from ca. 14 to 7 Ma (IV) and rapid uplift of two Himalayan syntaxes from ca. 6 to 2 Ma (V), respectively; (2) the coeval leucogranites emplaced in the Tethyan Himalayas (THLs) and Greater Himalayas (GHLs) had many similarities (particularly in Stages III and IV) in: geochemical compositions, peak emplacement ages, tectonic backgrounds, melting mechanisms, source domains, and fractional crystallization degrees; (3) materials from the Lesser Himalayan Sequence were increasingly significant in producing the HLs from the Eocene to the Pleistocene temporally, and from the Tethyan Himalayan Sequence to the Greater Himalayan Crystalline Complex spatially; (4) owing to the depleted abundances of rare-metal elements in mafic source rocks (e.g. amphibolites) and relatively lower fractional crystallization degrees of the Eocene leucogranites, rare-metal mineralization was rarely reported; (5) excessive fractional crystallization may be the dominant driving force for enriching rare-metal elements (Li-Be-Nb-Ta-W-Sn) of the HLs, making the Himalayas a new potential global orogen scale of polymetallic ore belt.

The widespread Cenozoic Himalayan leucogranites (HLs) are representative rocks evolving from relatively pure crust-derived melts with few mantle material inputs and are believed to be highly fractionated and rare-metal mineralization developed. Over the past several decades, high-quality geochronological and geochemical analyses for the HLs have facilitated exploring the metamorphism, deformation, anatexis, and tectonic settings, enabling us to decipher the evolution process of the Himalayan orogen. In this study, we collected a large amount of geochronological, geochemical, and thermodynamic data from previous studies. Generally, the HLs exhibit (strongly) peraluminous (1.06–1.22) features and are characterized by high SiO₂ (70.95–75.08 wt. %) and Al₂O₃ (14.18–15.85 wt. %) and low TiO₂ (0.02–0.26 wt. %), MgO (0.07–0.73 wt. %), MnO (0.01–0.07 wt. %), and total iron (FeO_T = 0.44–1.71 wt. %) contents, and are enriched in large ion lithophile elements (e.g. K, Rb, Pb, U). Moreover, rare-metal elements (Li, Be, Ta, W, Sn) also show their enrichments in the HLs; and the deviations of K/Rb (72.16–190.45), Zr/Hf (15.00–35.19), Nb/Ta (2.65–12.75), and Y/Ho (26.07–36.75) ratios from the chondritic values are also notable. All these geochemical structures above suggest that the HLs are (highly) fractionated. Considering the diverging whole-rock isotopic Sr and Nd compositions of the HLs, with the (⁸⁷Sr/⁸⁶Sr)_t ratios and εNd_(t) values mostly ranging from 0.7159 to 0.8052 and −16.78 to −10.43, respectively, the source rocks of the HLs should be multiplex. Additionally, different melting mechanisms (including fluid-absent/present partial melting of muscovite, biotite, and hornblende) can be identified in the HL productions. The occurrences of beryl (Be), columbite (Nb and Ta), spodumene (Li), and many other rare-metal minerals have been frequently reported recently, suggesting the enrichment of rare-metal elements associated with the HLs. To provide a comprehensive and meticulous summary of these HLs (1593 leucogranite samples), we divide them into five stages based on different tectonic backgrounds. After comparing them, we propose that: (1) from Stage I to V, the HL emplacements were strongly related to the tectonic backgrounds: thickened crust from ca. 49 to 40 Ma (I), transition from compression to N-S extension (onset of the South Tibetan Detachment System (STDS)) from ca. 39 to 30 Ma (II), large-scale N-S extension (active movement of the STDS) from ca. 29 to 15 Ma (III), N-S extension to E-W extension tectonic transition (construction of N-S trending rifts (NSTRs)) from ca. 14 to 7 Ma (IV) and rapid uplift of two Himalayan syntaxes from ca. 6 to 2 Ma (V), respectively; (2) the coeval leucogranites emplaced in the Tethyan Himalayas (THLs) and Greater Himalayas (GHLs) had many similarities (particularly in Stages III and IV) in: geochemical compositions, peak emplacement ages, tectonic backgrounds, melting mechanisms, source domains, and fractional crystallization degrees; (3) materials from the Lesser Himalayan Sequence were increasingly significant in producing the HLs from the Eocene to the Pleistocene temporally, and from the Tethyan Himalayan Sequence to the Greater Himalayan Crystalline Complex spatially; (4) owing to the depleted abundances of rare-metal elements in mafic source rocks (e.g. amphibolites) and relatively lower fractional crystallization degrees of the Eocene leucogranites, rare-metal mineralization was rarely reported; (5) excessive fractional crystallization may be the dominant driving force for enriching rare-metal elements (Li-Be-Nb-Ta-W-Sn) of the HLs, making the Himalayas a new potential global orogen scale of polymetallic ore belt.

The widespread Cenozoic Himalayan leucogranites (HLs) are representative rocks evolving from relatively pure crust-derived melts with few mantle material inputs and are believed to be highly fractionated and rare-metal mineralization developed. Over the past several decades, high-quality geochronological and geochemical analyses for the HLs have facilitated exploring the metamorphism, deformation, anatexis, and tectonic settings, enabling us to decipher the evolution process of the Himalayan orogen. In this study, we collected a large amount of geochronological, geochemical, and thermodynamic data from previous studies. Generally, the HLs exhibit (strongly) peraluminous (1.06–1.22) features and are characterized by high SiO₂ (70.95–75.08 wt. %) and Al₂O₃ (14.18–15.85 wt. %) and low TiO₂ (0.02–0.26 wt. %), MgO (0.07–0.73 wt. %), MnO (0.01–0.07 wt. %), and total iron (FeO_T = 0.44–1.71 wt. %) contents, and are enriched in large ion lithophile elements (e.g. K, Rb, Pb, U). Moreover, rare-metal elements (Li, Be, Ta, W, Sn) also show their enrichments in the HLs; and the deviations of K/Rb (72.16–190.45), Zr/Hf (15.00–35.19), Nb/Ta (2.65–12.75), and Y/Ho (26.07–36.75) ratios from the chondritic values are also notable. All these geochemical structures above suggest that the HLs are (highly) fractionated. Considering the diverging whole-rock isotopic Sr and Nd compositions of the HLs, with the (⁸⁷Sr/⁸⁶Sr)_t ratios and εNd_(t) values mostly ranging from 0.7159 to 0.8052 and −16.78 to −10.43, respectively, the source rocks of the HLs should be multiplex. Additionally, different melting mechanisms (including fluid-absent/present partial melting of muscovite, biotite, and hornblende) can be identified in the HL productions. The occurrences of beryl (Be), columbite (Nb and Ta), spodumene (Li), and many other rare-metal minerals have been frequently reported recently, suggesting the enrichment of rare-metal elements associated with the HLs. To provide a comprehensive and meticulous summary of these HLs (1593 leucogranite samples), we divide them into five stages based on different tectonic backgrounds. After comparing them, we propose that: (1) from Stage I to V, the HL emplacements were strongly related to the tectonic backgrounds: thickened crust from ca. 49 to 40 Ma (I), transition from compression to N-S extension (onset of the South Tibetan Detachment System (STDS)) from ca. 39 to 30 Ma (II), large-scale N-S extension (active movement of the STDS) from ca. 29 to 15 Ma (III), N-S extension to E-W extension tectonic transition (construction of N-S trending rifts (NSTRs)) from ca. 14 to 7 Ma (IV) and rapid uplift of two Himalayan syntaxes from ca. 6 to 2 Ma (V), respectively; (2) the coeval leucogranites emplaced in the Tethyan Himalayas (THLs) and Greater Himalayas (GHLs) had many similarities (particularly in Stages III and IV) in: geochemical compositions, peak emplacement ages, tectonic backgrounds, melting mechanisms, source domains, and fractional crystallization degrees; (3) materials from the Lesser Himalayan Sequence were increasingly significant in producing the HLs from the Eocene to the Pleistocene temporally, and from the Tethyan Himalayan Sequence to the Greater Himalayan Crystalline Complex spatially; (4) owing to the depleted abundances of rare-metal elements in mafic source rocks (e.g. amphibolites) and relatively lower fractional crystallization degrees of the Eocene leucogranites, rare-metal mineralization was rarely reported; (5) excessive fractional crystallization may be the dominant driving force for enriching rare-metal elements (Li-Be-Nb-Ta-W-Sn) of the HLs, making the Himalayas a new potential global orogen scale of polymetallic ore belt.