diff --git a/biology/py-macs3/Makefile b/biology/py-macs3/Makefile
index 9e80cf787df6..697cda306f9b 100644
--- a/biology/py-macs3/Makefile
+++ b/biology/py-macs3/Makefile
@@ -1,47 +1,49 @@
 PORTNAME=		MACS3
 DISTVERSIONPREFIX=	v
-DISTVERSION=		3.0.3
+DISTVERSION=		3.0.4
 CATEGORIES=		biology python
 PKGNAMEPREFIX=		${PYTHON_PKGNAMEPREFIX}
 
 MAINTAINER=	jwb@FreeBSD.org
 COMMENT=	Peak caller aimed at transcription factor binding sites
 WWW=		https://github.com/taoliu/MACS
 
 LICENSE=	BSD3CLAUSE
 LICENSE_FILE=	${WRKSRC}/LICENSE
 
 NOT_FOR_ARCHS=	i386
 NOT_FOR_ARCHS_REASON_i386=Requires _Float16
 
 COMMON_DEPENDS=	${PYNUMPY} \
 		${PYTHON_PKGNAMEPREFIX}scipy>1.11.1:science/py-scipy@${PY_FLAVOR} \
 		${PYTHON_PKGNAMEPREFIX}cykhash>=2.0,<3.0:devel/py-cykhash@${PY_FLAVOR} \
 		${PYTHON_PKGNAMEPREFIX}scikit-learn>=1.3:science/py-scikit-learn@${PY_FLAVOR} \
 		${PYTHON_PKGNAMEPREFIX}hmmlearn>=0.3.2:math/py-hmmlearn@${PY_FLAVOR}
 BUILD_DEPENDS=	${PYTHON_PKGNAMEPREFIX}wheel>0:devel/py-wheel@${PY_FLAVOR} \
+		${PYTHON_PKGNAMEPREFIX}setuptools>=0:devel/py-setuptools@${PY_FLAVOR} \
 		simde>0:devel/simde \
+		${PYTHON_PKGNAMEPREFIX}cython>0:lang/cython \
 		${COMMON_DEPENDS}
 RUN_DEPENDS=	${COMMON_DEPENDS}
 TEST_DEPENDS=	${PYTHON_PKGNAMEPREFIX}pytest>0:devel/py-pytest@${PY_FLAVOR} \
 		bash:shells/bash
 
 USES=		localbase perl5 python shebangfix
 USE_GITHUB=	yes
 USE_PERL5=	test
-USE_PYTHON=	autoplist concurrent cython distutils
+USE_PYTHON=	autoplist concurrent distutils
 
 GH_ACCOUNT=	macs3-project
 GH_PROJECT=	MACS
 SHEBANG_FILES=	test/cmdlinetest* test/prockreport test/*.py test/pyprofile*
 
 post-stage:
 	${STRIP_CMD} ${STAGEDIR}${PYTHON_SITELIBDIR}/MACS3/*/*.so
 
 # FIXME: Some tests fail due to a py-threadpoolctl issue
 # https://github.com/joblib/threadpoolctl/pull/148
 do-test: deinstall reinstall
 	@${RM} -rf ${WRKSRC}/temp
 	@cd ${WRKSRC}/test && ./cmdlinetest tag
 
 .include <bsd.port.mk>
diff --git a/biology/py-macs3/distinfo b/biology/py-macs3/distinfo
index f02adff90730..643ab3644b4e 100644
--- a/biology/py-macs3/distinfo
+++ b/biology/py-macs3/distinfo
@@ -1,3 +1,3 @@
-TIMESTAMP = 1740145847
-SHA256 (macs3-project-MACS-v3.0.3_GH0.tar.gz) = fb5cfe3d8189662b79df7c96f7782bc8327f1aafa61815a2ac86a8337917a558
-SIZE (macs3-project-MACS-v3.0.3_GH0.tar.gz) = 198064648
+TIMESTAMP = 1772212991
+SHA256 (macs3-project-MACS-v3.0.4_GH0.tar.gz) = e74ac701dbff16ea8dddc82d7431e8e6648a9fb2d99b8b7cd4fe6577f53692c8
+SIZE (macs3-project-MACS-v3.0.4_GH0.tar.gz) = 200470087
diff --git a/biology/py-macs3/files/patch-pyproject.toml b/biology/py-macs3/files/patch-pyproject.toml
index 262eb251f817..40c429df69a5 100644
--- a/biology/py-macs3/files/patch-pyproject.toml
+++ b/biology/py-macs3/files/patch-pyproject.toml
@@ -1,9 +1,17 @@
---- pyproject.toml.orig	2025-02-20 03:43:04 UTC
+--- pyproject.toml.orig	2026-02-22 22:11:36 UTC
 +++ pyproject.toml
 @@ -1,5 +1,5 @@
  [build-system]
--requires=['setuptools>=68.0', 'numpy>=1.25', 'scipy>=1.12', 'cykhash>=2.0', 'Cython>=3.0', 'scikit-learn>=1.3', 'hmmlearn>=0.3.2']
-+requires=['setuptools>=63.0', 'numpy>=1.25', 'scipy>=1.11.1', 'cykhash>=2.0', 'Cython>=0.29.37', 'scikit-learn>=1.3', 'hmmlearn>=0.3.2']
+-requires=['setuptools>=80.0', 'numpy>=1.25', 'scipy>=1.12', 'cykhash>=2.0', 'Cython>=3.0', 'scikit-learn>=1.3', 'hmmlearn>=0.3.2']
++requires=['setuptools>=63.0', 'numpy>=1.25', 'scipy>=1.11.1', 'cykhash>=2.0', 'Cython>=3.0', 'scikit-learn>=1.3', 'hmmlearn>=0.3.2']
  build-backend = "setuptools.build_meta"
  
  [project]
+@@ -10,7 +10,6 @@ requires-python = ">=3.9"
+ 	   {name = "Philippa Doherty", email = "Philippa.Doherty@RoswellPark.org"}]
+ readme = "README.md"
+ requires-python = ">=3.9"
+-license = "BSD-3-Clause"
+ classifiers =['Development Status :: 5 - Production/Stable',
+               'Environment :: Console',
+               'Intended Audience :: Developers',
diff --git a/biology/py-macs3/files/patch-requirements.txt b/biology/py-macs3/files/patch-requirements.txt
index 474854166d3c..4350e4b71051 100644
--- a/biology/py-macs3/files/patch-requirements.txt
+++ b/biology/py-macs3/files/patch-requirements.txt
@@ -1,14 +1,14 @@
---- requirements.txt.orig	2025-02-20 03:43:04 UTC
+--- requirements.txt.orig	2026-02-22 22:11:36 UTC
 +++ requirements.txt
 @@ -1,8 +1,8 @@
 -Cython>=3.0,<3.1
-+Cython>=0.29.37
++Cython>=3.0
  numpy>=1.25
 -scipy>=1.12
 +scipy>=1.11.1
  scikit-learn>=1.3
  hmmlearn>=0.3.2
  cykhash>=2.0,<3.0 
  pytest>=7.0
 -setuptools>=68.0
 +setuptools>=63.0