药学学报

DUB	Inhibitor	Mechanism	Development stage
USP5	Mebendazole	Targets the USP5/c-Maf axis, disrupting c-Maf transcription factor activity and suppressing cancer cell growth	Preclinical
USP7	P5091	Enhances Maf protein degradation and increases polyubiquitination levels	Preclinical
USP10	Spautin 1	Downregulation of the MM transcription factor IKZF1	Preclinical
USP14 UCHL5	VLX1570 (NCT02372240) b-AP15	Specific inhibition of deubiquitinases USP14 and UCHL5 associated with the 19S particle induces accelerated proteasome gate closure, resulting in a marked increase in polyubiquitin chain accumulation	Phase Ⅰ/Ⅱ clinical trial Preclinical

DUB

Inhibitor

Mechanism

Development stage

USP5

Mebendazole

Targets the USP5/c-Maf axis, disrupting c-Maf transcription factor activity and suppressing cancer cell growth

Preclinical

USP7

P5091

Enhances Maf protein degradation and increases polyubiquitination levels

Preclinical

USP10

Spautin 1

Downregulation of the MM transcription factor IKZF1

Preclinical

USP14
UCHL5

VLX1570 (NCT02372240)
b-AP15

Specific inhibition of deubiquitinases USP14 and UCHL5 associated with the 19S particle induces accelerated proteasome gate closure, resulting in a marked increase in polyubiquitin chain accumulation

Phase Ⅰ/Ⅱ clinical trial
Preclinical

DUB	Inhibitor	Mechanism	Development stage
USP5	Mebendazole	Targets the USP5/c-Maf axis, disrupting c-Maf transcription factor activity and suppressing cancer cell growth	Preclinical
USP7	P5091	Enhances Maf protein degradation and increases polyubiquitination levels	Preclinical
USP10	Spautin 1	Downregulation of the MM transcription factor IKZF1	Preclinical
USP14 UCHL5	VLX1570 (NCT02372240) b-AP15	Specific inhibition of deubiquitinases USP14 and UCHL5 associated with the 19S particle induces accelerated proteasome gate closure, resulting in a marked increase in polyubiquitin chain accumulation	Phase Ⅰ/Ⅱ clinical trial Preclinical

DUB

Inhibitor

Mechanism

Development stage

USP5

Mebendazole

Targets the USP5/c-Maf axis, disrupting c-Maf transcription factor activity and suppressing cancer cell growth

Preclinical

USP7

P5091

Enhances Maf protein degradation and increases polyubiquitination levels

Preclinical

USP10

Spautin 1

Downregulation of the MM transcription factor IKZF1

Preclinical

USP14
UCHL5

VLX1570 (NCT02372240)
b-AP15

Specific inhibition of deubiquitinases USP14 and UCHL5 associated with the 19S particle induces accelerated proteasome gate closure, resulting in a marked increase in polyubiquitin chain accumulation

Phase Ⅰ/Ⅱ clinical trial
Preclinical

Substance	Client protein	Molecular mechanism
Qurecetin	HSP27, HSP70, HSP90^[66]	HSP depletion and induction of apoptosis
KNK437	HSP105, HSP70, HSP40^[67]	Blocking the synthesis of inducible HSPs
Triptolide	HSP90^[68]	Inducing HSP90β phosphorylation at specific sites to facilitate apoptosome formation
KRIBB11	HSF1^[65]	Downregulating HSF1 downstream proteins
IHSF115	HSF1 DNA-binding domain^[69]	Inhibiting HSF1 transcriptional activity
DTHIB	HSF1 DNA-binding domain^[70]	Inducing degradation of the nuclear HSF1 protein
17-AAG	HSP90 ATP-binding site ^[71]	Disrupting the multi-chaperone complex and triggers HSP90's client protein degradation
Ganetespib	HSP90 ATP-binding site ^[72]	Disrupting HSP90's chaperone cycle
2, 4-Bis(4-hydroxybenzyl) phenol	HSF1^[73]	Reduced levels of HSF1 protein along with phosphorylation at multiple serine residues
Dorsomorphin	HSF1^[74]	Suppressing HSF1 activity by blocking its accumulation in the nucleus
Cantharidin	HSF1^[75]	Suppressing HSF1 independently of protein phosphatase 2A
Rohinitib	eIF4A^[76]	Inhibition of the translation initiation factor eIF4A leads to inactivation of HSF1

Substance

Client protein

Molecular mechanism

Qurecetin

HSP27, HSP70, HSP90^[66]

HSP depletion and induction of apoptosis

KNK437

HSP105, HSP70, HSP40^[67]

Blocking the synthesis of inducible HSPs

Triptolide

HSP90^[68]

Inducing HSP90β phosphorylation at specific sites to facilitate apoptosome formation

KRIBB11

HSF1^[65]

Downregulating HSF1 downstream proteins

IHSF115

HSF1 DNA-binding domain^[69]

Inhibiting HSF1 transcriptional activity

DTHIB

HSF1 DNA-binding domain^[70]

Inducing degradation of the nuclear HSF1 protein

17-AAG

HSP90 ATP-binding site ^[71]

Disrupting the multi-chaperone complex and triggers HSP90's client protein degradation

Ganetespib

HSP90 ATP-binding site ^[72]

Disrupting HSP90's chaperone cycle

2, 4-Bis(4-hydroxybenzyl) phenol

HSF1^[73]

Reduced levels of HSF1 protein along with phosphorylation at multiple serine residues

Dorsomorphin

HSF1^[74]

Suppressing HSF1 activity by blocking its accumulation in the nucleus

Cantharidin

HSF1^[75]

Suppressing HSF1 independently of protein phosphatase 2A

Rohinitib

eIF4A^[76]

Inhibition of the translation initiation factor eIF4A leads to inactivation of HSF1

Substance	Client protein	Molecular mechanism
Qurecetin	HSP27, HSP70, HSP90^[66]	HSP depletion and induction of apoptosis
KNK437	HSP105, HSP70, HSP40^[67]	Blocking the synthesis of inducible HSPs
Triptolide	HSP90^[68]	Inducing HSP90β phosphorylation at specific sites to facilitate apoptosome formation
KRIBB11	HSF1^[65]	Downregulating HSF1 downstream proteins
IHSF115	HSF1 DNA-binding domain^[69]	Inhibiting HSF1 transcriptional activity
DTHIB	HSF1 DNA-binding domain^[70]	Inducing degradation of the nuclear HSF1 protein
17-AAG	HSP90 ATP-binding site ^[71]	Disrupting the multi-chaperone complex and triggers HSP90's client protein degradation
Ganetespib	HSP90 ATP-binding site ^[72]	Disrupting HSP90's chaperone cycle
2, 4-Bis(4-hydroxybenzyl) phenol	HSF1^[73]	Reduced levels of HSF1 protein along with phosphorylation at multiple serine residues
Dorsomorphin	HSF1^[74]	Suppressing HSF1 activity by blocking its accumulation in the nucleus
Cantharidin	HSF1^[75]	Suppressing HSF1 independently of protein phosphatase 2A
Rohinitib	eIF4A^[76]	Inhibition of the translation initiation factor eIF4A leads to inactivation of HSF1

Substance

Client protein

Molecular mechanism

Qurecetin

HSP27, HSP70, HSP90^[66]

HSP depletion and induction of apoptosis

KNK437

HSP105, HSP70, HSP40^[67]

Blocking the synthesis of inducible HSPs

Triptolide

HSP90^[68]

Inducing HSP90β phosphorylation at specific sites to facilitate apoptosome formation

KRIBB11

HSF1^[65]

Downregulating HSF1 downstream proteins

IHSF115

HSF1 DNA-binding domain^[69]

Inhibiting HSF1 transcriptional activity

DTHIB

HSF1 DNA-binding domain^[70]

Inducing degradation of the nuclear HSF1 protein

17-AAG

HSP90 ATP-binding site ^[71]

Disrupting the multi-chaperone complex and triggers HSP90's client protein degradation

Ganetespib

HSP90 ATP-binding site ^[72]

Disrupting HSP90's chaperone cycle

2, 4-Bis(4-hydroxybenzyl) phenol

HSF1^[73]

Reduced levels of HSF1 protein along with phosphorylation at multiple serine residues

Dorsomorphin

HSF1^[74]

Suppressing HSF1 activity by blocking its accumulation in the nucleus

Cantharidin

HSF1^[75]

Suppressing HSF1 independently of protein phosphatase 2A

Rohinitib

eIF4A^[76]

Inhibition of the translation initiation factor eIF4A leads to inactivation of HSF1

高负荷蛋白稳态: 多发性骨髓瘤治疗的新兴靶点与研究进展

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郭梦婕 , 唐校柱 , 顾春艳 , 杨烨 ^*

药学学报 | 专题报道: 前沿靶标发现与重大疾病分子药理学机制研究 2026,61(6): 1935-1949

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药学学报 |专题报道: 前沿靶标发现与重大疾病分子药理学机制研究 2026 , 61 (6) : 1935 -1949

高负荷蛋白稳态: 多发性骨髓瘤治疗的新兴靶点与研究进展

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郭梦婕, 唐校柱, 顾春艳, 杨烨^*

作者信息

南京中医药大学医学院, 江苏南京 210023

通讯作者:

杨烨, E-mail: 290422@njucm.edu.cn

作者简介:

作者贡献:

郭梦婕在修稿过程中进行了大量的资料收集, 以及文章内容修改; 唐校柱负责资料收集与论文初稿撰写、论文撰写与图表绘制; 顾春艳、杨烨负责文章选题及论文指导与修改。

High-burden protein homeostasis: An emerging therapeutic target and research progress in multiple myeloma

Meng-jie GUO, Xiao-zhu TANG, Chun-yan GU, Ye YANG^*

Affiliations

School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China

出版时间: 2026-06-12 doi: 10.16438/j.0513-4870.2025-0582

文章导航

摘要

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多发性骨髓瘤(multiple myeloma, MM) 是一种起源于骨髓浆细胞的恶性血液系统肿瘤。该疾病特征为克隆性浆细胞的异常增生, 并伴有单克隆免疫球蛋白的过度分泌。高负荷蛋白稳态是多种恶性肿瘤的共同特征, 源于异常的蛋白质合成、折叠错误、蛋白质翻译后修饰(post-translational modifications, PTMs) 及蛋白质降解系统的功能失衡。这些特征涉及转录、剪接、翻译、翻译后修饰、降解过程及与骨髓微环境的相互作用。尽管蛋白质负荷对正常细胞具有毒性, 但对MM细胞而言, 却成为维持其快速增殖与存活的重要依赖。MM细胞长期大量分泌免疫球蛋白, 正是蛋白质高负荷促进肿瘤恶性演进的典型体现。本综述系统总结了当前获批及在研的MM治疗药物, 深入探讨维持蛋白质稳态的关键分子机制, 力图为开发以蛋白质高负荷为靶点的新型治疗策略提供理论依据。同时, 本文还探讨了蛋白翻译后修饰在MM蛋白质负荷形成中的关键作用。上述分析与中医“癌毒”理论在病因病机层面呈现高度契合, 为探索以“解毒”缓解蛋白质负荷的治疗路径, 提供了理论基础和实践方向。

关键词

多发性骨髓瘤 / 高负荷蛋白稳态 / 蛋白酶体 / 蛋白翻译后修饰 / 癌毒

Abstract

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Multiple myeloma (MM) is a malignant hematological cancer that originates from plasma cells in the bone marrow. The disease is characterized by abnormal proliferation of clonal plasma cells and excessive secretion of monoclonal immunoglobulin. High protein load is a common feature of various malignant tumors, resulting from abnormal protein synthesis, folding errors, post-translational modifications (PTMs), and imbalances in the protein degradation system. The bone marrow microenvironment also plays a role in these processes. Interestingly, while high protein levels are toxic to normal cells, cancer cells actually rely on this stress to grow and survive. MM cells, in particular, produce large amounts of immunoglobulins, which contribute to their malignant progression. This review provides a comprehensive overview of current and investigational treatments for MM, as well as the key molecular pathways involved in maintaining protein homeostasis. Special attention is given to the role of PTMs in shaping the high protein load phenotype in MM cells. These findings are in line with the traditional Chinese medicine concept of "cancer toxin" and may offer new insights for developing therapeutic strategies that target proteotoxic stress.

Key words

multiple myeloma / high-burden protein homeostasis / proteasome / post-translational modification / cancer toxin

引用本文

郭梦婕, 唐校柱, 顾春艳, 杨烨. 高负荷蛋白稳态: 多发性骨髓瘤治疗的新兴靶点与研究进展. 药学学报, 2026 , 61 (6) : 1935 -1949 . DOI: 10.16438/j.0513-4870.2025-0582

Meng-jie GUO, Xiao-zhu TANG, Chun-yan GU, Ye YANG. High-burden protein homeostasis: An emerging therapeutic target and research progress in multiple myeloma[J]. Acta Pharmaceutica Sinica, 2026 , 61 (6) : 1935 -1949 . DOI: 10.16438/j.0513-4870.2025-0582

正文

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多发性骨髓瘤(multiple myeloma, MM) 的致病核心在于肿瘤细胞异常高负荷的蛋白质合成, 特别是大量单克隆免疫球蛋白(M蛋白) 的产生。这导致MM细胞对蛋白酶体高度依赖, 其活性显著高于多种实体瘤细胞系^[1]。研究证实MM细胞中活跃的蛋白酶体亚基主要为β1、β2和β5, 且细胞因子刺激可进一步激活免疫蛋白酶体亚基^[2]。MM细胞对蛋白酶体抑制剂(proteasome inhibitor, PIs) 的敏感性源于其相对较低的蛋白酶体表达水平与持续高蛋白负荷(尤其是难以降解的异常M蛋白^[3]) 之间的失衡。这种失衡引发的“蛋白酶体应激”使MM细胞在蛋白酶体功能受阻时更易凋亡。值得注意的是, 尽管正常细胞在蛋白过载下也会凋亡, MM细胞却能在这种高负荷环境中存活增殖。这种蛋白质稳态(proteostasis) 的破坏, 即合成与降解失衡, 是MM等疾病的关键致病机制^[4]。

维持细胞功能依赖于对蛋白质合成、折叠、修饰和降解过程的精密调控, 确保蛋白质稳态的动态平衡^[5]。这一稳态由复杂的细胞内质量控制网络支撑, 核心包括热休克反应(heat shock response, HSR)、泛素-蛋白酶体系统(ubiquitin-proteasome system, UPS)、自噬-溶酶体通路(autophagy-lysosome pathway)、内质网质量控制(endoplasmic reticulum quality control, ERQC)、钙稳态调节及组蛋白去乙酰化酶(histone deacetylases, HDACs) 介导的调控等^[6]。其中, HSR、UPS、自噬系统和ERQC构成了蛋白质质量控制(protein quality control, PQC) 的核心网络, 负责识别并清除错误折叠或损伤的蛋白质, 防止其在细胞内聚集^[7]。这些调控机制的失衡导致异常蛋白积聚, 是癌症、神经退行性疾病等重大疾病发生的共同病理基础^[8]。

MM治疗的演进深刻体现了靶向蛋白质稳态的策略。多数有效治疗手段均干预蛋白过载状态, 尤以PIs (直接靶向UPS) 和自噬激活剂(增强降解能力) 为代表。基于此, 本文结合本课题组及国内外研究, 提出并深化了“高负荷蛋白稳态” (high-burden proteostasis) 理论。该理论强调, 在高蛋白负荷压力下, MM细胞高度依赖特定的PQC机制(如特定的蛋白酶体亚基活性) 维持生存。尤为关键的是, 本文从蛋白质翻译后修饰(post-translational modifications, PTMs) 视角深化了该理论, 揭示泛素化、乙酰化、磷酸化等PTMs在调控MM相关蛋白(包括癌蛋白和应激反应蛋白) 稳定性与功能状态中的核心作用。

这一理论发展不仅为中医“癌毒理论”提供了现代分子生物学基础, 更开辟了以PTMs为靶点的新治疗路径。通过识别并干扰MM细胞对特定PTMs的依赖性, 有望实现更精准、持久的抗肿瘤效果, 展现出广阔的应用前景。

1　蛋白质稳态调控药物的研究进展

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1.1　PIs疗法

细胞内蛋白质降解主要通过UPS完成, 该过程在维持蛋白质稳态、调节信号通路及清除异常蛋白方面发挥着核心作用^[9]。蛋白降解过程始于泛素(ubiquitin, Ub) 被泛素激活酶(E1) 激活, 形成E1-Ub复合物。随后, 活化的泛素通过硫酯键转移至泛素结合酶(E2), 并在泛素连接酶(E3) 的催化下与底物蛋白共价结合, 形成多泛素链标记。这些被泛素标记的底物蛋白随后被26S蛋白酶体识别, 经过解聚后降解为短肽片段, 从而完成对靶蛋白的特异性清除(图1A)^[10]。硼替佐米(bortezomib) 是首个获批上市的二肽硼酸类蛋白酶体抑制剂, 被誉为蛋白酶体靶向治疗的开创性成果^[11]。第二代蛋白酶体抑制剂卡非佐米(carfilzomib) 为环肽酮类药物, 作用更为强效, 能够不可逆地与β5亚基活性位点的丝氨酸残基结合, 彻底阻断蛋白酶体功能^[12]。伊沙佐米(ixazomib) 则作为首个口服蛋白酶体抑制剂, 突破了传统静脉给药的局限性, 极大提升了患者的治疗依从性和生活质量^[13]。这3种代表性PIs在血液系统肿瘤的治疗中已取得显著成果, 为MM及相关疾病患者带来了新的治疗希望(图1B)。靶向蛋白质降解的治疗策略尤其适用于对UPS高度依赖的肿瘤类型。如在淋巴瘤中, NF-κB信号通路通常处于持续激活状态, 而PIs (如硼替佐米) 可通过阻断IκB降解, 间接抑制NF-κB活性, 发挥抗肿瘤作用^[14]。然而, 在MM中, 相关机制则表现出显著差异。有研究发现, 硼替佐米可诱导IκBβ和受体相互作用蛋白2 (RIP2) 的磷酸化, 反而激活NF-κB通路, 提示其抗MM机制可能并不依赖NF-κB的经典抑制^[15]。目前PIs的临床应用仍主要集中于血液系统恶性肿瘤。

1.2　E3泛素连接酶调节剂

来那度胺(lenalidomide) 作为沙利度胺(thalidomide) 的结构优化衍生物, 是E3连接酶调节剂中最具代表性的药物之一, 已为MM及多种难治性疾病患者带来新的希望^[16]。目前已鉴定出约650种E3泛素连接酶, 其中约40%参与UPS介导的蛋白降解过程。E3泛素连接酶作为关键调控因子, 在DNA损伤修复、转录调控及细胞信号转导等核心生物学过程中起决定性作用, 其功能异常已被证实与多种人类恶性肿瘤的发生发展密切相关^[17]。一方面, 一些E3泛素连接酶可介导肿瘤抑制因子的降解, 从而促进肿瘤发生。与此相对, 另一些E3泛素连接酶则具备肿瘤抑制功能, 通过促进致癌蛋白的降解来抑制肿瘤进展^[18] (图1C)。Cereblon (CRBN) 是该类E3泛素连接酶的代表, 广泛表达于肝脏、肾脏等组织。来那度胺及其新一代衍生物如泊马度胺(pomalidomide) 即是通过与CRBN结合, 诱导特定靶蛋白(如IKZF1/3) 的降解, 从而发挥免疫调节与抗肿瘤作用^[19]。CC-92480 (mezigdomide) 是新一代CRBN调节剂, 对IKZF1/3的降解活性更强, 针对高度耐药MM (如来那度胺/泊马度胺耐药) 显示潜力^[19]。CC-220 (iberdomide) 可以优化CRBN结合能力, 增强免疫调节作用, 探索用于MM和自身免疫疾病。这两种药物目前都在临床试验中^[20]。这一类E3泛素连接酶调节剂是临床中唯一获批用于淋巴瘤及MM治疗的药物类别, 其成功应用也为下一代靶向蛋白降解药物的开发提供了理论基础与实践路径。

1.3　去泛素化酶(deubiquitinating enzymes, DUBs) 抑制剂

DUBs通过调控多种蛋白质的命运, 在多个细胞过程中的作用深远。如去泛素化酶USP7可稳定癌蛋白MYC, 后者是驱动肿瘤增殖和转移的关键因子之一^[21]。相反, 其他DUBs则通过保护抑癌蛋白免受降解而发挥抑癌作用。以USP10为例, 它可稳定肿瘤抑制因子p53, 防止其被蛋白酶体降解, 从而维持细胞稳态^[22]。USP9X和JOSD2等DUBs通过正向调控YAP/TAZ蛋白的去泛素化, 增强其稳定性与功能, 从而促进肿瘤发展^[23]。USP1可去泛素化Fanconi贫血相关蛋白, 从而增强其修复DNA损伤的能力^[24]。相反, USP37通过稳定CDT1蛋白可引发过度DNA复制, 导致基因组不稳定^[25]。此外, USP9X和USP10还参与SMAD4的去泛素化调控^{[26, 27]}。特别的是, DUBs已成为程序性细胞死亡的重要调控因子, 其通过影响调控细胞凋亡的蛋白质的稳定性与功能来发挥作用^[28]。DUBs可以通过调控促凋亡与抗凋亡蛋白的泛素化水平, 进而促进或抑制细胞凋亡。如USP2一方面可通过稳定cFLIP蛋白发挥促生存作用^[29], 这种稳定作用可抑制Caspase-8的二聚化和激活, 从而抑制凋亡发生; 另一方面, USP2也可通过促进cyclin D1的泛素化诱导细胞凋亡^[30]。DUBs在癌细胞中的异常表达, 加之其高度特异的催化结构域, 使其成为小分子抑制剂的理想靶点。DUB抑制剂是一类能够直接结合DUB催化位点的小分子化合物, 有效阻断其酶活性, 被形象地称为“分子破坏者”^[31]。通过精准干预异常激活的DUB, 这些抑制剂有望恢复细胞内泛素化信号通路的正常运行, 从源头上遏制病理性蛋白积聚与功能紊乱(表1、图1D)。目前, VLX1570和KSQ-4279是最具代表性的DUB抑制剂。VLX1570于2015年进入MM患者的Ⅰ/Ⅱ期临床试验(NCT02372240), 作为首个进入临床阶段的DUB抑制剂, 主要靶向USP14和UCHL5等蛋白酶体相关DUBs, 通过抑制其降解受损蛋白的能力, 诱导细胞毒性蛋白积累, 从而促进肿瘤细胞凋亡^[32]。2017年, 另一款候选药物USP1抑制剂KSQ-4279进入临床试验, 靶向BRCA缺陷型晚期实体瘤患者(NCT05240898)^[33]。USP1是调控DNA损伤应答(DNA-damage response, DDR) 和同源重组修复(homologous recombination, HR) 通路的关键因子, 尤其在Fanconi贫血修复通路中扮演重要角色。KSQ-4279通过抑制USP1, 削弱肿瘤细胞对DNA损伤的耐受性, 特别适用于对PARP抑制剂耐药或携带DDR缺陷的肿瘤患者^[33]。USP7可以调控p53、MDM2等关键蛋白的稳定性, 抑制USP7可激活p53通路^[34]。最新研究显示, FT-671是一种选择性USP7抑制剂, 干扰其去泛素化活性, 导致下游靶蛋白的泛素化降解^[35], 其对于MM的疗效研究目前处于临床前研究阶段。总的来看, 尽管DUB抑制剂的开发仍面临选择性差、靶点验证不足及毒性控制等诸多挑战, 但其在蛋白质稳态调控和靶向治疗中的独特作用机制, 展现出巨大的临床转化潜力。

1.4　蛋白降解靶向嵌合体(proteolysis-targeting chimeras, PROTACs): 靶向蛋白降解的革命性策略

PROTAC技术能够降解许多传统意义上“不可药物化”的蛋白质, 这类蛋白因结构复杂或功能重要而难以通过常规药物干预^[36]。2019年, 首个双功能PROTAC降解剂ARV-110进入临床, 用于治疗转移性去势抵抗性前列腺癌^[37]。迄今为止, 已有15种PROTAC药物进入临床试验阶段, 靶点各异, 治疗策略多样^{[36, 38]}。与传统小分子药物仅抑制蛋白功能不同, PROTACs可通过诱导靶蛋白降解, 提供更直接、有效的治疗手段。PROTAC分子通过连接E3泛素连接酶与目标蛋白, 形成三元复合物, 实现精准降解且不良反应较小^[39] (图1E)。PROTACs在克服长期用药耐药性方面展现出潜力。以BCR-ABL为靶点, Yu等^[40]通过将达沙替尼或博舒替尼与CRBN配体结合, 成功降解BCR-ABL蛋白。值得注意的是, BCR-ABL过表达及T315I突变是导致耐药的关键因素。针对这一难题, Yang等^[41]开发了能同时靶向3个不同药物结合位点的PROTAC分子, 其中P19P可有效降解T315I和V468F耐药突变体, 并减少泊那替尼的不良反应。PROTACs已成功应用于PI3K的降解。Li等^[42]通过连接泊马度胺与哌嗪衍生物, 设计了一系列新型PI3K-PROTACs。Zorba等^[43]合成了11种PROTAC, 并研究了它们降解BTK的能力。他们发现, 连接子的长度对于促进BTK与CRBN之间的相互作用至关重要。NX-2127是一种口服BTK靶向降解剂, 可同时降解野生型BTK及C481S突变体, 用于复发/难治性B细胞恶性肿瘤治疗^[44]。CFT7455是靶向IKZF1/3的monoDAC降解剂, 具有治疗MM的潜力^[45]。尽管PROTAC具有诸多优势, 其应用仍面临一些挑战。早期PROTAC多以肽为基础配体, 但其稳定性和穿透性较差, 限制了临床应用^[46]。为解决这一问题, 研究人员开发出具有更强活性、更佳细胞穿透性及更低免疫原性的PROTAC分子^[47], 如基于CRBN的PROTACs在多个疾病模型中显示出良好疗效。随后又开发出以VHL为E3连接酶配体的PROTACs, 其在靶向多种致病蛋白方面展现出显著的特异性与活性^[39]。这些小分子PROTAC设计的进展, 为靶向更广泛蛋白(如RIPK2/ERRα、BRD4) 奠定了基础, 并拓展了其在多种疾病治疗中的潜力^[48]。

1.5　分子胶: 突破蛋白质相互作用的新策略

分子胶是一种单价小分子(< 500 Da), 通过改变E3连接酶表面结构, 阻断其与天然底物的结合, 并诱导特定靶蛋白与E3连接酶结合, 进而促使靶蛋白泛素化并被蛋白酶体降解。该技术基于UPS, 是靶向蛋白质降解的重要方法之一^[49]。与PROTAC不同, 分子胶可直接介导蛋白质之间的相互作用, 诱导靶蛋白泛素化并降解^[49], 且分子量更小, 成药性也更高, 在透膜性和生物利用度上更具优势(图1F)。目前, 分子胶的研究仍主要集中在少数靶点上, 大部分进入临床试验的分子胶药物是在偶然情况下被发现, 主要集中于IKZF1/3和GSPT1^[50]。沙利度胺是首个被证实通过结合E3泛素连接酶CRBN来调控蛋白稳定性的分子胶, 可诱导多种底物蛋白发生泛素化降解^[51]。目前, 全球共有3款分子胶药物获批上市, 包括沙利度胺、来那度胺和泊马度胺。这些药物在实体瘤(如黑色素瘤、前列腺癌和分化型甲状腺癌) 及血液系统恶性肿瘤中疗效显著, 已获美国FDA批准用于治疗MM等疾病^[52]。截至当前, 最前沿的分子胶类药物已进入Ⅱ期临床试验阶段^[53]。其中, CC-90009通过介导GSPT1与CRBN的结合, 触发GSPT1的蛋白酶体依赖性降解过程, 从而引发急性髓性白血病(acute myeloid leukemia, AML) 细胞的凋亡^[54]。CC-92480和CFT7455均为CRBN (E3泛素连接酶) 的调节剂, 可介导IKZF1/3的降解, 主要用于治疗难治性MM^{[19, 45]}。其中, CFT7455已获得美国FDA的“孤儿药”资格认证; 而临床数据显示, CC-92480在治疗剂量下的客观缓解率达到48%。Mezigdomide (MEZI) 是一种高效cereblon E3连接酶调节剂(cereblon E3 ligase modulator, CELMoD), 它能最大化降解锌指转录因子Ikaros/Aiolos, 显著增强MM细胞凋亡。临床前研究证实, MEZI与地塞米松(dexamethasone, DEX)、PIs及抗CD38单抗联用可产生协同抗肿瘤作用^[55]。KPG-818作为CRL4-CRBN复合物的E3泛素连接酶调节剂, 对CRBN靶点具有极高亲和力, 可有效降解IKZF3/IkZF1转录因子。Ⅰ期临床试验显示, 该药物在复发/难治性MM患者中安全性良好, 耐受性优异, 药代动力学特征理想, 并展现出显著的治疗潜力。

1.6　热休克蛋白抑制剂: 抗癌潜力与临床挑战

在高温等环境应激下, 细胞会激活一种称为HSR的保护机制, 其特征是基因表达的显著变化^[56]。该反应的核心调节因子是热休克蛋白(heat shock proteins, HSPs)。与正常细胞相比, 癌细胞对HSPs依赖性更高。这些分子伴侣参与癌症的多种进程, 包括增殖、转移与侵袭, 其在多种恶性肿瘤中的高表达常与患者不良预后相关, 如肺癌、胃癌和乳腺癌^[57]。其中, HSP90和HSP70作为热休克反应的核心组成部分, 能够稳定和调节多个癌蛋白(如p53突变体和HER2) 表达, 显著促进肿瘤发生和发展^[58]。此外, HSP70和HSP27还能通过干扰促凋亡蛋白表达、降低胞内游离钙水平、稳定溶酶体等机制抑制肿瘤细胞凋亡^[59]。天然产物格尔德霉素(geldanamycin) 是第一代HSP抑制剂^[60], 但其存在溶解性差、肝毒性强等缺点, 还可能通过旁路机制上调HSP70和HSP90表达, 从而引起耐药性^[61]。为此, 研究人员通过结构改造开发出17-AAG和17-DMAG等衍生物, 这些化合物在一定程度上提高了稳定性和降低了毒性^[62], 但仍未能解决HSP70和HSP90适应性上调的问题。第二代抑制剂如AUY922、STA9090、PU-3和XL888, 有效解决了该难题, 部分药物已进入临床试验阶段^[63] (图1G)。针对热休克转录因子1 (heat shock transcription factor 1, HSF1) 的癌症疗法仍处于临床前阶段, 但已被认为是癌症治疗的一种很有前景的方式。HSF1是一种无配体的转录因子, 其“成药性”较差^[64]。近期报道的直接HSF1抑制剂, 如DTHIB和CCT361814, 为HSF1药物研发带来了新的希望。这两种抑制剂在临床前动物研究中显示出对肿瘤生长的高效抑制作用和高特异性, 同时对正常组织的毒性较低^[65]。令人鼓舞的是, CCT361814已进入Ⅰ期临床试验。各类热休克蛋白抑制剂见表2^[65-76]。

1.7　自噬-溶酶体靶向降解技术: 多靶点协同高效降解的新策略

在现有策略基础上, 越来越多新颖的蛋白稳态调控方法正在变革抗癌药物研发路径, 为开发PROTAC等蛋白调控剂带来新视角。随着对自噬-溶酶体系统(autophagy-lysosomal system, ALS) 研究的深入, 基于溶酶体途径的蛋白质降解正展现出比传统蛋白酶体路径更广泛的应用前景, 因后者主要限于胞内蛋白降解^[77]。溶酶体靶向嵌合体(lysosome-targeting chimera, LYTAC) 是新兴的一类蛋白降解工具, 能突破传统PROTAC无法靶向膜/胞外蛋白的限制^[78]。目前, LYTAC可结合3类靶蛋白配体: 抗体、小分子及短肽^[78]。然而, 抗体的组织穿透性较差, 小分子难以靶向“不可成药”蛋白, 相比之下, 短肽因合成简便、结构灵活而成为更具前景的选择^[79]。如一种与西妥昔单抗(Erbitux^®) 偶联的LYTAC可特异性降解EGFR^[80], 另一种与抗PD-L1抗体偶联的LYTAC则可促进PD-L1的溶酶体降解^[81]。近年来, 基于自噬-溶酶体机制的新型降解剂不断涌现, 包括自噬体绑定化合物(autophagosome-tethering compound, ATTEC)、自噬靶向嵌合体(autophagy-targeting chimera, AUTAC) 和自噬体拴系化合物(autophagosome-tethering compound, AUTOTAC) 等^[82]。ATTEC通过直接结合自噬受体LC3, 触发细胞内蛋白质和非蛋白质物质的降解。AUTAC则利用K63连接的多泛素化标记来实现选择性蛋白降解。AUTOTAC则依赖SQSTM1/p62复合物介导自噬降解过程。这3种降解剂通过不同机制清除异常蛋白、蛋白聚集体和功能失调的细胞器, 具有治疗多种疾病的潜力^[83]。以AUTOTAC为例, 其结构包含自噬靶向配体(autophagy-targeting ligand, ATL) 和靶结合配体(target-binding ligand, TBL), 能同时结合靶蛋白和SQSTM1/p62, 形成可被LC3识别的复合物, 从而通过自噬途径降解Tau样蛋白等致病蛋白^[84]。在靶蛋白降解技术飞速发展的今天, 相比PROTACs, 这3种新型自噬降解剂具有更广泛的靶标谱和更高的效能, 可以解决单一靶标易产生的耐药问题, 为包括MM在内的肿瘤提供了突破耐药瓶颈的新思路, 未来需通过临床验证其安全性和联合用药潜力, 同时开发预测性生物标志物以指导个体化治疗。

2　蛋白质翻译后修饰是维持高负荷蛋白稳态的关键调控机制

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本课题组研究发现, 蛋白质甲基化和泛素化等PTMs不仅维持MM细胞内的蛋白质过载, 还直接促进MM细胞增殖, 是疾病发生的关键因素。PTMs作为调控蛋白质稳态的关键环节, 能够显著影响蛋白质的丰度、构象与功能状态^[85]。越来越多的证据表明, PTMs不仅是对蛋白质表面的“修饰”, 更是一种动态可塑的“分子密码”, 可决定蛋白质的相互作用模式、亚细胞定位及生物活性, 从而精细地调控细胞信号转导、周期调控、凋亡等多种生命活动^[85]。这种复杂而精确的翻译后调控机制, 使得细胞能够在应对内外环境变化时保持功能稳定性, 并对微环境刺激做出快速适应(图2)。

PTM酶类就像分子层面的雕塑家, 主要可分为3类: 负责添加化学修饰的“写入者” (writers), 负责识别并解读修饰信息并启动下游信号通路的“阅读者” (readers), 以及负责去除修饰、动态调控蛋白功能的“清除者” (erasers)^[86]。单一的蛋白质位点可被多种不同的修饰作用, 这些修饰之间可能相互协调或竞争, 影响蛋白质的功能和相互作用; 同时, 单一的PTM调控酶也可根据细胞环境的不同, 发挥添加、识别或去除修饰的不同功能^[[87]。PTMs可激活或抑制信号通路、改变蛋白质-蛋白质相互作用、调控蛋白稳定性, 如同分子开关一般, 调控细胞对环境刺激、生长因子和应激信号的响应^[88] (图3)。

随着研究者对PTM信号网络理解的不断深入, 未来有望发展出针对PTM调控酶或异常修饰模式的创新治疗策略^[89]。近年来, 基于高分辨率质谱(high-resolution mass spectrometry, HRMS) 的蛋白质组学技术在定量研究组蛋白H3修饰标记方面发挥了重要作用^[90]。除已广泛研究的PTMs外, 一些高频但尚未被充分探索的修饰类型也逐渐受到关注。尽管目前已鉴定出超过300种不同的PTMs, 但由于技术限制, 仅有少数在蛋白质组层面得到系统研究。MM细胞因大量分泌单克隆免疫球蛋白(M蛋白), 面临独特的蛋白稳态压力^[3]: ①内质网应激: 未折叠蛋白反应(unfolded protein response, UPR) 的IRE1-XBP1通路常被激活, 但持续应激可能导致细胞凋亡; ②蛋白酶体依赖: MM细胞对蛋白酶体抑制剂敏感, 但耐药性可能通过聚集小体(aggresome) 形成或自噬途径代偿; ③分子伴侣网络: HSP90、HSP70等伴侣蛋白在MM中高表达, 成为潜在靶点。PIs (如硼替佐米) 是临床基石, 但耐药性问题突出。PTMs和高负荷蛋白稳态是MM的关键弱点, 但也是治疗耐药的主要屏障。本团队关于PTMs在MM中的作用研究总结如下。

2.1　通过甲基化修饰调控高负荷蛋白稳态

课题组以“以毒攻毒”理论为指导, 选取来源于传统中药雄黄的活性小分子三氧化二砷作为探针, 该化合物具有明确的抗MM活性。课题组联合多组学技术, 利用人源化蛋白质芯片和覆盖2 000余例MM与结直肠癌(colorectal cancer, CRC) 患者的转录组数据库, 开展高通量靶点筛选, 最终识别出甘氨酰胺核糖核苷酸甲酰转移酶(glycinamide ribonucleotide transformylase, GART) 作为三氧化二砷的潜在靶点^[91]。本研究创新性地发现了GART具有崭新的甲基转移酶功能, 其酶活性中心位于GART蛋白的E948位点。机制研究表明, GART通过其全新甲基转移酶活性, 促进RuvB like AAA ATPase 1 (RUVBL1) 蛋白K7位点甲基化以增强其蛋白稳定性, 从而异常激活Wnt/β-catenin信号通路诱导MM和CRC干性^{[91, 92]}。基于“老药新用”的思路, 本团队与临床团队合作, 将已上市的靶向GART药物培美曲塞(pemetrexed) 成功转化应用于临床, 已惠及包括CRC和MM在内的10余位患者。

2.2　通过分子伴侣共激活因子AHA1调控高负荷蛋白稳态

秉持“以毒攻毒”理念, 本团队继续挖掘与其他类型PTMs有关的MM新型治疗靶点。聚焦来源于传统中药“蟾酥”的活性小分子活性成分蟾毒灵(bufalin), 通过高通量筛选技术, 从大量潜在靶点中识别出分子伴侣共激活因子AHA1作为bufalin的关键作用靶点。作为“蛋白加工厂”HSP90分子伴侣复合物的激活因子, AHA1通过激活HSP90, 进而促进CDK6磷酸化, 最终引发MM细胞恶性增殖。AHA1对维持MM细胞蛋白过载(特别是CDK6等细胞周期蛋白激活) 发挥重要作用。基于这一发现, 进一步探讨抑制AHA1作为治疗MM的新策略。本团队首次合成了AHA1的小分子抑制剂KU-177, KU-177在体内外展现出显著的抗肿瘤活性, 不仅有效抑制MM细胞增殖, 还能逆转耐药^[93]。

2.3　通过蛋白质泛素化调控高负荷蛋白稳态

泛素-蛋白酶体系统可主导蛋白质半衰期稳定性命运。因此, 在深入挖掘MM患者样本的转录组数据库过程中, 本研究团队开展了一项高通量筛选探索, 旨在揭示MM复杂分子图谱中潜藏的与泛素化/类泛素化修饰有关的治疗靶点。基于高通量筛选结果, 本团队系统解析了E3泛素蛋白连接酶RFWD2在MM中的精密作用机制, 发现该因子在诱导对硼替佐米(一线治疗药物) 产生耐药性方面发挥重要作用。此前的研究已证实, RFWD2能够保护MM细胞免于硼替佐米诱导的蛋白酶体降解, 从而使肿瘤细胞逃避死亡, 继续恶性增殖^[94]。通过精确挖掘临床样本数据库, 并结合当前临床治疗背景, 本课题组进一步证实: 由RFWD2主导的泛素修饰过程不仅是维持MM细胞蛋白质负荷过载的关键因素, 更在推动疾病进展中发挥核心作用^[94]。蛋白质负荷过载作为MM的典型特征之一, 其持续存在加剧了细胞应激和病程演变。这一突破性发现不仅将RFWD2确立为一个全新的治疗靶点, 也强调了泛素化修饰作为MM发病机制关键调控因子的深远意义, 为靶向干预策略提供了理论基础与实践方向。

2.4　通过蛋白质乙酰化调控高负荷蛋白稳态

蛋白质乙酰化是一种重要的翻译后修饰, 由乙酰辅酶A提供乙酰基团, 在赖氨酸乙酰转移酶(lysine acetyltransferases, KATs) 的催化作用下实现^[95]。最初发现于组蛋白, 该修饰调控染色质状态和基因表达。与组蛋白去乙酰化酶(histone deacetylases, HDACs) 共同维持动态平衡, 其作用已扩展到多种非组蛋白^[96], 包括代谢酶和结构蛋白, 通过调节活性、稳定性及相互作用精确控制细胞功能, 在蛋白质稳态中发挥重要作用。本团队继续聚焦于蛋白质乙酰化与蛋白稳态在MM发生发展中的作用研究, 发现N4-乙酰胞苷(ac4C) 是一种由NAT10催化形成的古老且高度保守的RNA表观遗传修饰^[97], 是目前mRNA中唯一被发现的乙酰化修饰形式, 其在MM中的作用未有研究报道。机制研究发现, NAT10通过增强CEP170的mRNA乙酰化水平促进其蛋白翻译, 进而促进MM细胞容错分裂, 维持MM细胞蛋白严重过载的作用机制^[98]。此外, 本团队还阐明细胞因子AIMP1介导H3组蛋白乙酰化, 促进MM细胞恶性增殖的机制^[99]。这些发现表明乙酰化修饰作为MM蛋白稳态调控的“分子开关”, 其研究不仅深化了对疾病机制的理解, 也为开发新型联合疗法提供了契机。

2.5　通过SUMO化调控高负荷蛋白稳态

除了前文提到的多种PTMs外, UPS系统同样受到一类较大分子量的多肽类修饰的调控。这些修饰包括小泛素样修饰蛋白(ubiquitin-like proteins, UBLs), 如SUMO (小泛素样修饰物)、NEDD8、ISG15、UFM1和URM1等。通过改变蛋白质的分子互作环境, 这些UBLs能够影响其与降解相关因子的结合, 从而调节其命运^[100]。在这一过程中, 特异性识别SUMO化底物的酶系统会将其标记为泛素化对象, 进而引导其蛋白酶体降解^[101]。如SUMO E3连接酶对PML-RAR蛋白的SUMO化修饰, 使其被哺乳动物中主要的泛素样连接酶RNF4识别, 继而被泛素化并通过蛋白酶体途径降解^[102]。除直接促进底物降解外, SUMO还可通过间接方式调控蛋白质稳定性。课题组运用“毒性中药”秋水仙中的活性小分子成分秋水仙碱为探针, 通过蛋白芯片高通量筛选发现SAE1 (SUMO激活酶亚基1) 为秋水仙碱潜在新靶标, 并进一步证明了秋水仙碱通过靶向SAE1, 干预SAE1介导的MM增殖。研究发现: SAE1通过SUMO化修饰p27, 促进其发生液-液相分离, 影响p27在细胞核内外的定位, 使“经典抑癌基因”p27发挥促癌作用, 推动MM细胞恶性增殖^[103]。因此, SUMO修饰网络在MM中整合了蛋白稳态、基因组维护和微环境交互, 是一个极具潜力的治疗靶标。

2.6　通过氧化调控高负荷蛋白稳态

蛋白质氧化在MM中扮演着重要的角色, 其作用机制涉及氧化应激导致的蛋白质损伤、细胞信号通路紊乱及肿瘤微环境的调控, 最终影响MM的进展、治疗耐药和预后^[104]。蛋白质氧化是指蛋白质分子在活性氧(reactive oxygen species, ROS) 或活性氮(reactive nitrogen species, RNS) 等氧化性分子的作用下, 发生共价修饰或结构改变的过程。这是一类典型的非酶促翻译后修饰(non-enzymatic PTM), 通常发生在蛋白质的特定氨基酸残基上, 如半胱氨酸(cysteine, Cys)、甲硫氨酸(methionine, Met)、酪氨酸(tyrosine, Tyr)、色氨酸(tryptophan, Trp) 和组氨酸(histidine, His) 等^[105]。团队首次发现雷公藤的主要功效物质雷公藤红素垂钓出的MM新靶标磷酸吡哆醇氧化酶(PNPO), 证实PNPO氧化DVL3蛋白M282位点增强其与GSK3β的结合, 从而异常激活Wnt/β-catenin信号并上调c-Myc基因表达。这一通路的激活将维持蛋白过载, 最终增强MM细胞增殖能力的作用机制。艾曲波帕“老药新用”靶向PNPO, 同时抑制MM细胞和破骨细胞中PNPO蛋白, “一石二鸟”干预MM微环境^[106]。

2.7　降解信号位点(degron) 处多种PTMs之间的串扰——以MYC和p53为例

根据上述总结的PTM类型, 目前已实验鉴定的PTM位点数量远超人类编码蛋白基因的总数, 这凸显了多种修饰形式之间复杂的交互作用在调控蛋白质功能方面的重要性。因此, “PTM网络”的概念逐渐受到重视, 即不同类型的修饰通过协同或拮抗机制共同影响蛋白的行为, 包括其降解稳定性等。然而, 由于技术和研究手段的限制, 目前对这些网络的系统性刻画仍较为有限, 只有在如MYC和p53等研究较充分的蛋白上取得了较为清晰的进展。

2.7.1　多种PTMs对MYC稳定性的调控

MYC的异常高表达是多种癌症的标志性特征。作为强效致癌基因, MYC蛋白的表达需受到多重降解机制的精细调控, 以避免细胞异常增殖。其中一条核心机制是通过T58和S62位点的磷酸化以及P63位点的脯氨酸异构化调节其稳定性^[107]。这些修饰由多种激酶、磷酸酶和异构酶协同完成, 共同决定MYC的降解与活性状态。以T58为核心的“磷酸化降解信号” (phospho-degron) 是MYC降解的关键节点, 且受到其他PTM的复杂调节^[108]。如SUMO E3连接酶PIAS1可在K52位点对MYC进行SUMO化, 增强JNK1介导的S62磷酸化, 同时抑制T58位点的磷酸化, 从而间接影响MYC的稳定性。尽管如此, K52突变型MYC的降解并不完全依赖于FBXW7, 提示可能还存在其他E3连接酶或替代机制^[109]。此外, MYC的稳定性还受到多种泛素E3连接酶及其他PTMs的调控。乙酰化作为一种重要修饰, 可由CBP、p300、GCN5、PCAF和TIP60等酶催化, 部分抑制MYC的泛素化降解, 从而稳定其蛋白水平^[110]。相反, 去乙酰化酶SIRT1则可促使MYC去乙酰化并加速其降解。然而, 这些乙酰化修饰如何精确影响MYC的稳定性, 目前仍未完全阐明。值得注意的是, HDAC抑制剂的处理会诱导MYC超乙酰化, 进而加速降解, 提示MYC蛋白周转存在复杂的调控网络^[111]。

2.7.2　p53稳定性的调控实例

p53在超过50%的癌症中失活, 是细胞应对基因毒性应激的核心调控因子^[112]。目前已鉴定出p53上约300个PTM位点, 是已知修饰最丰富的蛋白之一, 其功能的多样性正是由这些修饰的动态协调所赋予。鉴于p53调控机制的研究文献极为庞杂, 本节仅选取部分代表性实例进行讨论。p53是一种短寿命肿瘤抑制因子, 其活化通常伴随蛋白稳定性的提升。虽然已发现30余种调控p53的E3连接酶, MDM2仍是最具代表性的泛素连接酶, 其识别p53 N端18~28位氨基酸进行泛素化, 从而介导蛋白酶体降解^[113]。p53的C端还包含6个位点的赖氨酸残基, 是其主要的泛素化靶点。DNA损伤可诱导S15和T18位点的磷酸化, 破坏MDM2与p53的结合, 从而稳定p53。与此同时, C端赖氨酸的乙酰化也能对抗泛素化并增强p53的稳定性^[114]。研究发现, N端磷酸化与C端乙酰化之间存在协同作用, 可共同促进p53的稳定化。此外, SUMO化和甲基化等其他修饰也参与调控p53的稳定性与转录活性^[115]。此外, 类似于S15磷酸化可募集CBP, SETD7对K372的甲基化也被认为有助于p53结合染色质, 并促进TIP60的募集及其对C端其他位点的乙酰化^[116]。但SETD7介导的K372甲基化在p53调控中的具体作用仍存争议, 不同小鼠模型与细胞实验对其影响存在相互矛盾的结果, 增加了解释的复杂性。尽管多种PTM已被证实参与调控p53的稳定性与功能, 但其潜在的分子机制仍有待深入探索。

3　总结与展望

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近年来, 在MM的诊断、治疗和管理方面取得了显著进展, 改善了患者预后并延长了生存期。然而, MM仍然是一种难以治愈的疾病, 其根本障碍在于MM蛋白负荷过重。为应对这一挑战, 当前研究的重点正在转向开发新型的蛋白相关治疗策略, 以缓解蛋白负荷带来的病理影响。尽管在该领域已取得一定进展, 但由于MM本身的高度复杂性, 仍需持续探索新的治疗手段以有效干预蛋白超负荷状态。

错误折叠蛋白的积聚会触发UPR, 细胞通过一系列机制尝试恢复蛋白稳态。然而, UPR的持续激活可能导致细胞凋亡或恶性转化。肿瘤细胞通常代谢异常, 表现为蛋白合成加快而降解机制减弱, 从而导致蛋白质负荷加剧。这类异常积聚的错误折叠蛋白可被视为一种特殊的“毒素”, 不仅对细胞本身造成损害, 还可诱发免疫反应, 进而促进肿瘤的发生与进展。蛋白负荷可引起细胞功能障碍、遗传变异, 甚至推动细胞的恶性转化。中医认为, “毒邪”损伤正气, 可导致气血失调、脏腑功能失常, 最终发展为肿瘤。因此, 现代医学中的“蛋白负荷”概念与传统中医学中的“癌毒”理论具有高度契合性。基于前期研究成果, 如MM靶标SAE1为SUMO修饰, PNPO为氧化修饰等, 提示MM靶标多与PTMs相关, 同时MM病理特征之一是大量分泌M蛋白, 本团队提出“蛋白严重过载”为MM癌毒物质基础。在MM细胞中, M蛋白异常积聚导致代谢亢进, 形成局部邪实病理状态。这些细胞通过重编程代谢途径持续掠夺机体能量, 一方面支持MM细胞的恶性增殖和促癌代谢产物生成; 另一方面不断化生癌毒、痰浊、瘀血、热邪等病理产物。随着病程进展, 逐渐形成元气耗损、瘤体毒邪壅聚、瘤周正气虚衰的虚实错杂病机格局^[117]。中医通过清热解毒、活血化瘀、扶正祛邪等方法, 有效干预蛋白负荷, 从而达到治疗肿瘤的目的^[118]。如秋水仙碱靶向SAE1影响其SUMO化修饰干预MM的临床疗效, 本团队与南通大学附属医院血液科合作, 秋水仙碱“老药新用”于50余例MM患者, 患者临床症状(指标) 明显改善, 无进展生存期显著延长^[103]。将中医的“癌毒”理论与现代医学的“蛋白负荷”概念相结合, 为理解肿瘤发生发展机制提供了新的视角。通过深入研究两者的内在联系, 有望更加全面地认识肿瘤本质, 进而开发出更具靶向性的治疗策略。

蛋白质负荷的发生过程离不开PTMs的调控, 这也是MM蛋白负荷病理生理学的重要特征之一。PTMs调控蛋白稳定性的多样机制反映出细胞信号网络的复杂性。尽管目前对磷酸化激活或抑制的降解信号(degrons) 已有深入研究, 但近年来发现的甲基化相关降解信号仍有待进一步探索。此外, 最新研究表明, PTMs还可通过影响相分离现象, 调节蛋白质的稳定性^[119], 如通过隔离E3泛素连接酶与底物的方式来改变降解效率。基于PTMs的蛋白稳定性调控为肿瘤治疗提供了新的靶点机会。许多致癌蛋白(如转录因子) 由于结构无序, 缺乏传统意义上的可成药位点, 难以直接靶向。然而, 催化PTMs的酶类通常具有明确的结合口袋, 因此更易成为药物开发靶标。如致癌转录因子MYC的降解依赖于PP2A介导的去磷酸化, 激活PP2A的策略可能成为治疗MYC驱动型肿瘤的新途径^[120]。

尽管针对PTMs的药物在临床前和部分临床试验中显示出良好疗效, 但其向临床转化仍面临诸多挑战, 主要包括: 如何解析代谢相关PTMs与先天/获得性免疫在肿瘤发生与治疗中的交互关系; 如何预测PTMs对高度异质且具可塑性的肿瘤微环境(tumor microenvironment, TME) 中补偿性通路的具体影响; 如何明确PTM抑制剂作用后产生的关键药物靶标与生物机制, 以及如何设计高效的早期临床研究, 系统评估PTM调控及TME重塑对抗肿瘤治疗效果的影响等。

随着对PTMs生物学功能认识的不断深入, PTMs在维持高负荷蛋白稳态中的核心地位愈发凸显。特别是在MM等以蛋白质产生与分泌高度活跃为特征的恶性肿瘤中, PTMs不仅调控蛋白质的稳定性、定位与功能, 还通过精密的修饰网络, 维系细胞对蛋白质过载的适应能力。这一机制在肿瘤细胞应对内质网应激、氧化损伤及代谢紊乱等复杂环境中, 发挥着至关重要的“应激缓冲”作用。

未来研究可进一步挖掘不同类型PTMs (如泛素化、甲基化、乙酰化、磷酸化、SUMO化等) 在特定信号轴上的动态交叉调控机制, 以揭示其在蛋白稳态维持中的层级结构和关键节点。同时, 针对特定PTMs的靶向干预策略(如修饰酶激动剂/抑制剂、小分子降解剂、分子胶技术等) 有望成为突破MM耐药和复发的全新治疗途径。为克服肿瘤异质性和耐药性, 可将蛋白稳态靶向药物(如蛋白酶体抑制剂、分子伴侣抑制剂) 与其他机制药物(如免疫调节剂、CD38单抗、BCMA靶向疗法) 联用。利用质谱技术监测治疗前后蛋白稳态相关蛋白的动态变化, 指导靶点选择。为提高药物递送和选择性, 开发肿瘤特异性递送系统, 如纳米颗粒包裹药物以增强骨髓渗透。为解决新型靶点的临床转化受限于毒性或疗效不足问题, 运用PROTACs、LYTAC技术优化靶点选择与药物设计, 同时采用“老药新用”策略^[121]。值得期待的是, 随着组学技术(如proteoform测序、PTM质谱谱图分析) 和人工智能辅助药物筛选平台的快速发展, 未来研究人员有望实现对PTMs网络的系统解码, 并据此构建精准调控高负荷蛋白稳态的“图谱式治疗”策略, 为MM等以蛋白稳态紊乱为特征的肿瘤提供更高效、个性化的治疗方案。

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2026年第61卷第6期

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doi: 10.16438/j.0513-4870.2025-0582

接收时间：2025-05-22
首发时间：2026-09-21
出版时间：2026-06-12

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收稿日期：2025-05-22
修回日期：2025-07-30

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南京中医药大学医学院, 江苏南京 210023

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杨烨, E-mail: 290422@njucm.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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DUB	Inhibitor	Mechanism	Development stage
USP5	Mebendazole	Targets the USP5/c-Maf axis, disrupting c-Maf transcription factor activity and suppressing cancer cell growth	Preclinical
USP7	P5091	Enhances Maf protein degradation and increases polyubiquitination levels	Preclinical
USP10	Spautin 1	Downregulation of the MM transcription factor IKZF1	Preclinical
USP14 UCHL5	VLX1570 (NCT02372240) b-AP15	Specific inhibition of deubiquitinases USP14 and UCHL5 associated with the 19S particle induces accelerated proteasome gate closure, resulting in a marked increase in polyubiquitin chain accumulation	Phase Ⅰ/Ⅱ clinical trial Preclinical

DUB

Inhibitor

Mechanism

Development stage

USP5

Mebendazole

Targets the USP5/c-Maf axis, disrupting c-Maf transcription factor activity and suppressing cancer cell growth

Preclinical

USP7

P5091

Enhances Maf protein degradation and increases polyubiquitination levels

Preclinical

USP10

Spautin 1

Downregulation of the MM transcription factor IKZF1

Preclinical

USP14
UCHL5

VLX1570 (NCT02372240)
b-AP15

Specific inhibition of deubiquitinases USP14 and UCHL5 associated with the 19S particle induces accelerated proteasome gate closure, resulting in a marked increase in polyubiquitin chain accumulation

Phase Ⅰ/Ⅱ clinical trial
Preclinical

Substance	Client protein	Molecular mechanism
Qurecetin	HSP27, HSP70, HSP90^[66]	HSP depletion and induction of apoptosis
KNK437	HSP105, HSP70, HSP40^[67]	Blocking the synthesis of inducible HSPs
Triptolide	HSP90^[68]	Inducing HSP90β phosphorylation at specific sites to facilitate apoptosome formation
KRIBB11	HSF1^[65]	Downregulating HSF1 downstream proteins
IHSF115	HSF1 DNA-binding domain^[69]	Inhibiting HSF1 transcriptional activity
DTHIB	HSF1 DNA-binding domain^[70]	Inducing degradation of the nuclear HSF1 protein
17-AAG	HSP90 ATP-binding site ^[71]	Disrupting the multi-chaperone complex and triggers HSP90's client protein degradation
Ganetespib	HSP90 ATP-binding site ^[72]	Disrupting HSP90's chaperone cycle
2, 4-Bis(4-hydroxybenzyl) phenol	HSF1^[73]	Reduced levels of HSF1 protein along with phosphorylation at multiple serine residues
Dorsomorphin	HSF1^[74]	Suppressing HSF1 activity by blocking its accumulation in the nucleus
Cantharidin	HSF1^[75]	Suppressing HSF1 independently of protein phosphatase 2A
Rohinitib	eIF4A^[76]	Inhibition of the translation initiation factor eIF4A leads to inactivation of HSF1

Substance

Client protein

Molecular mechanism

Qurecetin

HSP27, HSP70, HSP90^[66]

HSP depletion and induction of apoptosis

KNK437

HSP105, HSP70, HSP40^[67]

Blocking the synthesis of inducible HSPs

Triptolide

HSP90^[68]

Inducing HSP90β phosphorylation at specific sites to facilitate apoptosome formation

KRIBB11

HSF1^[65]

Downregulating HSF1 downstream proteins

IHSF115

HSF1 DNA-binding domain^[69]

Inhibiting HSF1 transcriptional activity

DTHIB

HSF1 DNA-binding domain^[70]

Inducing degradation of the nuclear HSF1 protein

17-AAG

HSP90 ATP-binding site ^[71]

Disrupting the multi-chaperone complex and triggers HSP90's client protein degradation

Ganetespib

HSP90 ATP-binding site ^[72]

Disrupting HSP90's chaperone cycle

2, 4-Bis(4-hydroxybenzyl) phenol

HSF1^[73]

Reduced levels of HSF1 protein along with phosphorylation at multiple serine residues

Dorsomorphin

HSF1^[74]

Suppressing HSF1 activity by blocking its accumulation in the nucleus

Cantharidin

HSF1^[75]

Suppressing HSF1 independently of protein phosphatase 2A

Rohinitib

eIF4A^[76]

Inhibition of the translation initiation factor eIF4A leads to inactivation of HSF1